Medicinal Chemistry
Medicinal Chemistry in NIPER JEE covers pharmacophore identification, structure–activity relationships, physicochemical properties, prodrugs, bioisosterism, enzyme/receptor inhibitors, and QSAR.
Core rules and concepts
- Oral drug-likeness: Lipinski rule of five - MW ≤500, cLogP ≤5, HBD ≤5, HBA ≤10. Violations are counted; two or more predict poor oral absorption.
- Pharmacophore is the spatial arrangement of essential features (H-bond donor/acceptor, hydrophobic, aromatic, ionic), not a single functional group.
- Bioisosteres: –COOH ↔ tetrazole; –OH ↔ –NH2; –H ↔ –F; ester ↔ amide; phenyl ↔ thiophene. They retain activity while changing metabolism, pKa, or solubility.
- Prodrugs are inactive derivatives converted in vivo: ester prodrugs are hydrolyzed by esterases; enalapril is hydrolyzed to enalaprilat; sulfasalazine is cleaved by colonic bacteria.
- Hansch QSAR: log(1/C) = a logP + bσ + c; σ is the Hammett electronic constant. Correlation is valid only within the applicability domain.
Worked example
A candidate has MW 480, cLogP 4.8, HBD 4, HBA 9. All four limits are satisfied: 480 ≤500, 4.8 ≤5, 4 ≤5, 9 ≤10. The compound has zero Lipinski violations. If HBD were 6, it would have one violation; adding a carboxylic acid (HBD +1, HBA +2) may push HBA to 11 and produce a second violation, flagging likely poor oral absorption.
Traps that cost marks
- Treating Lipinski rules as proof of activity; they only estimate permeability/oral absorption.
- Confusing logP (neutral species) with logD (pH-dependent distribution coefficient).
- Assuming every prodrug is active before metabolism; most are not.
- Ignoring stereochemistry: enantiomers can differ in potency and metabolism.