Pharmacoinformatics approach to the discovery of novel selective COX-2 inhibitors by in silico virtual screening

Various potent anti-cancer compounds, defined as group A, B, D, and YC-1 derivatives, were recruited for the simulation trails of selective inhibition to human cyclooxygenase-2 (COX-2). From our modeling, Leu530 and Ile522 would lead to the COX-1 binding site with a tunnel-like configuration. Compounds of group B would be suitable in the lobby of COX-1. In contract, the larger compounds, group A, D, and YC-1 derivatives were more potential against COX-2. As more the compounds bound in the similar pose indicates more the possible docking poses could happen, and thus generated the consensus pose. The anthraquinonyl group could be more suitable near the Tyr371 and Trp373 of COX-2, and the added hydroxyl group that interacted with Arg106/Tyr341 gate led the ligand more stable. In aspect of group D, the fused hydroxyl and aldehydyl group on one candidate attempted to interact with the gate which induced the whole construction more stable. Besides, the hydrophobic groups, fusing on some candidates and bounding between Ser516 and Tyr371 could stabilize the whole conformations in active site. We found the H-bond interactions between the gate of active site and the hydrophobic region among Ser516 and Tyr371 were important for the bound ligands in COX-2 active site.