Comparative in silico evaluation of selective and preferential COX-2 inhibitors: Insights from molecular docking,...

Selective COX-2 inhibition is a key strategy for inflammation management. Using an integrative multi-scale computational workflow that includes docking, MM-GBSA, Molecular Dynamics (MD), ADMET, and toxicity profiling, this study differentiates highly selective inhibitors (celecoxib, etoricoxib) from preferential agents (meloxicam, etodolac). Highly selective coxibs demonstrated superior COX-2 affinity (ΔG_bind -58.05 to -67.12 kcal/mol) by anchoring rigid pharmacophores into the Val-523 side pocket via specific hydrogen bonding with Ile-517 and Phe-518, leading to complete steric exclusion from COX-1. In contrast, preferential inhibitors rely primarily on Arg-120 gatekeeper interactions. While both classes demonstrate hydrophobic engagement with Val-523, the preferential agents notably lack the critical side-pocket hydrogen bonds found in the coxib class. Meloxicam's conformational plasticity facilitates docking into the constricted COX-1 channel, explaining its lower selectivity ratio. Toxicity profiling predicted celecoxib to possess the most favorable acute safety margin (GHS Class 5), while meloxicam exhibited the narrowest predicted therapeutic index (GHS Class 3/4). These results suggest that scaffold rigidity and specific side-pocket bonding are the primary determinants of isoform exclusivity. This study provides a structure-guided mechanistic framework for elucidating the pharmacological diversity and safety of COX-2 inhibitors.