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