Deciphering the mechanism behind the varied binding activities of COXIBs through Molecular Dynamic Simulations, MM-PBSA binding energy calculations and per-residue energy decomposition studies

COX-2 is a well-known drug target in inflammatory disorders. COX-1/COX-2 selectivity of NSAIDs is crucial in assessing the gastrointestinal side effects associated with COX-1 inhibition. Celecoxib, rofecoxib, and valdecoxib are well-known specific COX-2 inhibiting drugs. Recently, polmacoxib, a COX-2/CA-II dual inhibitor has been approved by the Korean FDA. These COXIBs have similar structure with diverse activity range. Present study focuses on unraveling the mechanism behind the 10-fold difference in the activities of these sulfonamide-containing COXIBs. In order to obtain insights into their binding with COX-2 at molecular level, molecular dynamics simulations studies, and MM-PBSA approaches were employed. Further, per-residue decomposition of these energies led to the identification of crucial amino acids and interactions contributing to the differential binding of COXIBs. The results clearly indicated that Leu338, Ser339, Arg499, Ile503, Phe504, Val509, and Ser516 (Leu352, Ser353, Arg513, Ile517, Phe518, Val523, and Ser530 in PGHS-1 numbering) were imperative in determining the activity of these COXIBs. The binding energies and energy contribution of various residues were similar in all the three simulations. The results suggest that hydrogen bond interaction between the hydroxyl group of Ser516 and five-membered ring of diarylheterocycles augments the affinity in COXIBs. The SAR of the inhibitors studied and the per-residue energy decomposition values suggested the importance of Ser516. Additionally, the positive binding energy obtained with Arg106 explains the binding of COXIBs in hydrophobic channel deep in the COX-2 active site. The findings of the present work would aid in the development of potent COX-2 inhibitors.