Medicinal Chemistry and Drug Action
Core concepts
Understand structure–activity relationships (SAR): how functional groups, stereochemistry, lipophilicity (logP), pKa, and hydrogen bonding alter receptor binding, absorption, and metabolism. Know the physicochemical rules - Lipinski's rule of five (MW ≤500, logP ≤5, H-bond donors ≤5, acceptors ≤10), and how ionisation at physiological pH affects distribution. Familiarise yourself with pharmacophores of major classes: beta-lactams (beta-lactam ring essential), statins (HMG-CoA-like pharmacophore), benzodiazepines (7-chloro, 5-phenyl substitution), and sulfonamides (para-amino group). Understand prodrug design (masking polar groups to improve absorption, e.g., ester prodrugs), bioisosterism, and metabolic soft spots.
Traps
Stereochemistry is a frequent trap: enantiomers can differ in activity (S- vs R- warfarin, thalidomide). Do not confuse logP (partition) with logD (distribution at a given pH). Adding a polar group usually decreases CNS penetration. Metabolism often occurs at lipophilic sites; blocking a metabolic soft spot prolongs half-life. Prodrugs have no intrinsic activity until converted.
Worked rule of thumb
If a question asks why a drug has poor oral bioavailability despite good receptor affinity, suspect high polarity/ionisation (low logP at gut pH) or first-pass metabolism - esterification or a bioisostere often fixes it.
Exam strategy
Link each structural feature to a property: binding (efficacy), lipophilicity (absorption/CNS), ionisable group (solubility), metabolic site (half-life).