Celecoxib preferentially inhibits COX-2 over COX-1. Which structural feature of COX-2 allows selective inhibitors to bind?
- A An extra disulfide bond in COX-2's active site
- B A serine residue at position 530 unique to COX-2 that forms covalent bond with the drug
- C A larger hydrophobic side-pocket in COX-2 due to substitution of Val523 (in COX-1) with Ile523, creating additional binding space ✓
- D A smaller active site in COX-2 that excludes non-selective NSAIDs
Correct answer: C. A larger hydrophobic side-pocket in COX-2 due to substitution of Val523 (in COX-1) with Ile523, creating additional binding space
Explanation
In COX-2, isoleucine at position 523 (versus valine in COX-1) creates a larger hydrophobic side-pocket at the active site. Selective COX-2 inhibitors (coxibs) have bulky sulphonamide or sulphone groups that fit into this side-pocket in COX-2 but are excluded from the tighter COX-1 active site, conferring selectivity. Aspirin acetylates Ser530 in both isoforms (non-selective). The other options are pharmacologically incorrect.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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