Celecoxib selectively inhibits COX-2 over COX-1. The structural basis for this selectivity involves:
- A Celecoxib is a larger molecule that cannot access the smaller COX-1 active site channel
- B COX-2 has lower affinity for arachidonic acid allowing competitive displacement by celecoxib
- C A unique side pocket in COX-2 (Val523 instead of Ile523) accommodating celecoxib's sulfonamide group ✓
- D Celecoxib acetylates the COX-2 serine residue irreversibly while COX-1 lacks this serine
Correct answer: C. A unique side pocket in COX-2 (Val523 instead of Ile523) accommodating celecoxib's sulfonamide group
Explanation
COX-2 differs from COX-1 in having valine (Val523) at a position where COX-1 has isoleucine (Ile523). This smaller side chain creates an additional hydrophobic side pocket in the COX-2 active site. Celecoxib and other COX-2 selective inhibitors are designed with a bulky sulfonamide or sulfone group that fits precisely into this COX-2-specific side pocket, conferring selectivity. COX-1 cannot accommodate this substituent due to the larger isoleucine residue.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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