Hermes-agent

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+# ADMET Reference Guide
+
+Comprehensive reference for Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis in drug discovery.
+
+## Drug-Likeness Rule Sets
+
+### Lipinski's Rule of Five (Ro5)
+
+| Property | Threshold |
+|----------|-----------|
+| Molecular Weight (MW) | ≤ 500 Da |
+| Lipophilicity (LogP) | ≤ 5 |
+| H-Bond Donors (HBD) | ≤ 5 |
+| H-Bond Acceptors (HBA) | ≤ 10 |
+
+Reference: Lipinski et al., Adv. Drug Deliv. Rev. 23, 3–25 (1997).
+
+### Veber's Oral Bioavailability Rules
+
+| Property | Threshold |
+|----------|-----------|
+| TPSA | ≤ 140 Å² |
+| Rotatable Bonds | ≤ 10 |
+
+Reference: Veber et al., J. Med. Chem. 45, 2615–2623 (2002).
+
+### CNS Penetration (BBB)
+
+| Property | CNS-Optimal |
+|----------|-------------|
+| MW | ≤ 400 Da |
+| LogP | 1–3 |
+| TPSA | < 90 Å² |
+| HBD | ≤ 3 |
+
+## CYP450 Metabolism
+
+| Isoform | % Drugs | Notable inhibitors |
+|---------|---------|-------------------|
+| CYP3A4 | ~50% | Grapefruit, ketoconazole |
+| CYP2D6 | ~25% | Fluoxetine, paroxetine |
+| CYP2C9 | ~15% | Fluconazole, amiodarone |
+| CYP2C19 | ~10% | Omeprazole, fluoxetine |
+| CYP1A2 | ~5% | Fluvoxamine, ciprofloxacin |
+
+## hERG Cardiac Toxicity Risk
+
+Structural alerts: basic nitrogen (pKa 7–9) + aromatic ring + hydrophobic moiety, LogP > 3.5 + basic amine.
+
+Mitigation: reduce basicity, introduce polar groups, break planarity.
+
+## Common Bioisosteric Replacements
+
+| Original | Bioisostere | Purpose |
+|----------|-------------|---------|
+| -COOH | -tetrazole, -SO₂NH₂ | Improve permeability |
+| -OH (phenol) | -F, -CN | Reduce glucuronidation |
+| Phenyl | Pyridine, thiophene | Reduce LogP |
+| Ester | -CONHR | Reduce hydrolysis |
+
+## Key APIs
+
+- ChEMBL: https://www.ebi.ac.uk/chembl/api/data/
+- PubChem: https://pubchem.ncbi.nlm.nih.gov/rest/pug/
+- OpenFDA: https://api.fda.gov/drug/
+- OpenTargets GraphQL: https://api.platform.opentargets.org/api/v4/graphql