Medicinal Chemistry and Drug Design
What the exam tests
Medicinal Chemistry and Drug Design tests structure–activity relationships, physicochemical properties, prodrug strategy, and the logic of lead optimization.
Core rules
- Lipinski rule of five for oral drug-likeness: MW at most 500, logP at most 5, H-bond donors at most 5, H-bond acceptors at most 10. It is a heuristic, not a pass/fail law; antibiotics and transporter substrates are exceptions.
- Bioisosteres replace groups with similar size and electronics: a carboxylic acid with tetrazole, a hydroxyl with amino, or a phenyl ring with thiophene. The aim is to retain activity while changing metabolism or solubility.
- Prodrugs mask a problematic group. Enalapril is an ester prodrug hydrolyzed to enalaprilat; the ester improves absorption, but the active drug is the acid.
- Ionization: for a weak base, fraction protonated = 1/(1 + 10^(pH − pKa)); for a weak acid, fraction ionized = 1/(1 + 10^(pKa − pH)).
Worked example
A weak base has pKa 8.4. At plasma pH 7.4, pH − pKa = −1.0, so the BH+/B ratio is 10^(pKa − pH) = 10^1 = 10. The protonated fraction is 10/11 = 0.909, or 91%. Because the charged form is less membrane-permeable, this compound is largely trapped in plasma and extracellular fluid relative to a more basic or neutral analogue; if the target is intracellular, that distribution matters.
Traps
Do not count every nitrogen as a hydrogen-bond donor; amides are weak acceptors and poor donors. Do not assume a prodrug is inactive without checking the conversion route. Do not optimize logP without checking aqueous solubility and CYP inhibition. Do not ignore stereochemistry: enantiomers can differ in affinity and clearance.