Rationale for the observed COX-2/COX-1 selectivity of celecoxib from Monte Carlo simulations

Computational studies have yielded an analysis of the contributions to the free energy difference between the binding of celecoxib to COX-1 and to COX-2. The energetic and structural results point to the Ile to Val mutation at residue 523 as the key contributor to COX-2 selectivity; unfavorable steric contact between a sulfonamide oxygen and the δ methyl group of Ile523 destabilizes the complex with COX-1. The His to Arg change at residue 513 is less significant.