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. 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. The His to Arg change at residue 513 is less significant.