Medicinal Chemistry and Drug Design
Medicinal Chemistry and Drug Design tests structure–activity relationships, pharmacophore recognition, physicochemical optimization, and metabolic stability. The exam favors mechanistic reasoning: why a functional group change alters potency, selectivity, or pharmacokinetics.
Core rules
- A pharmacophore is the spatial arrangement of features required for activity, not the whole molecule.
- Bioisosteres replace groups with similar size or electronics: carboxylic acid with tetrazole; hydroxyl with amino; chlorine with methyl; sulfide with oxygen. They can improve metabolic stability or acidity without abolishing binding.
- Lipinski's rule of five is a screening heuristic: molecular weight ≤500, logP ≤5, hydrogen-bond donors ≤5, acceptors ≤10. It predicts poor oral absorption probability, not a legal cutoff.
- Prodrugs are inactive derivatives requiring biotransformation: enalapril to enalaprilat, valacyclovir to acyclovir. Ester prodrugs improve oral absorption but may be hydrolyzed presystemically.
- Stereochemistry matters: enantiomers can differ in receptor affinity, metabolism, and toxicity.
Worked example
A carboxylic acid lead is potent but too polar and has poor oral bioavailability. Replacing the carboxylic acid with a tetrazole keeps acidity and hydrogen bonding and often improves pharmacokinetics. Reasoning: tetrazole is a bioisostere, not a prodrug; it does not require activation. If the carboxylate is essential for a salt bridge, the change may reduce potency, so test both target binding and Caco-2 permeability.
Traps
Treating Lipinski violations as absolute disqualification; assuming a prodrug is active in vitro; ignoring that a bioisostere can change selectivity; forgetting that racemic assays can hide enantiomer-specific effects.