Structure-Activity Relationships and Drug Design
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Lesson 2 of 12
Notes
Structure-Activity Relationships (SAR)
SAR is the relationship between a drug's chemical structure and its pharmacological activity. Understanding SAR enables medicinal chemists to modify lead compounds to improve potency, selectivity, pharmacokinetics, or reduce toxicity. The pharmacophore is the minimal structural feature essential for receptor binding — the three-dimensional arrangement of atoms (hydrogen bond donors/acceptors, charged groups, hydrophobic regions) required for activity.
Key SAR principles: (1) Isosteric replacement — substituting atoms or groups of similar size and electronic character (e.g., F for H, S for O) to alter metabolic stability or binding; (2) Bioisosteres — groups with similar biological properties, e.g. tetrazole as a carboxylic acid bioisostere in losartan; (3) Homologation — adding CH2 groups to explore optimal chain length; (4) Ring closure — cyclising a flexible chain increases rigidity and may improve selectivity; (5) Prodrugs — inactive precursors converted in vivo to active drug, improving bioavailability, masking toxicity, or enabling site-specific delivery.
Beta-Lactam Antibiotics
Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems) inhibit bacterial transpeptidase (penicillin-binding proteins, PBPs), preventing peptidoglycan cross-linking in the cell wall. The beta-lactam ring is the pharmacophore — its carbonyl binds covalently to the serine residue of PBPs. Modifications to the side chain determine spectrum (e.g., amoxicillin's amino group improves gram-negative activity). Beta-lactamase resistance is overcome by beta-lactamase inhibitors (clavulanic acid — acts as a suicide substrate), or through structural modification (carbapenems are poor beta-lactamase substrates).
Benzodiazepines
Benzodiazepines act as positive allosteric modulators of GABA-A receptors, enhancing chloride channel opening frequency. The pharmacophore is the 1,4-benzodiazepine scaffold with a phenyl ring at position 5 and an aryl or heteroaryl at position 7 (electron-withdrawing substituent essential). Lipophilicity determines onset and duration: diazepam (high logP) — rapid onset, long duration (active metabolites); lorazepam (intermediate logP) — no active metabolites, suitable for hepatic impairment. Flumazenil is a competitive antagonist at the same site.