hermes-agent/optional-skills/research/drug-discovery/references/ADMET_REFERENCE.md

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 Ų
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 Ų
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