Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2)

Molecular models of the complex between the selective COX-2 inhibitor nimes ulide and the cyclooxygenase active site of human prostaglandin-endoperoxid e synthase-2 have been built using a combination of homology modelling, con formational searching and automated docking techniques. The stability of th e resulting complexes has been assessed by molecular dynamics simulations a nd interaction energy decomposition. It is found that nimesulide exploits t he extra space made available by the replacement at position 523 of an isol eucine residue in COX-1 by a valine in COX-2 and establishes electrostatic interactions with both Arg-106 and Arg-499 (Arg-120 and Arg-513 in PGHS-1 n umbering). Two alternate binding modes are proposed which are compatible wi th the pharmacological profile of this agent as a COX-2 selective inhibitor .