Molecular modeling study of COX-2 inhibition by diarylheterocycles and sulindac sulfide

The inducible form of cyclooxygenase, prostaglandin G/H synthase-2 (PGHS-2, COX-2), is inhibited by sulindac sulfide and more selectively inhibited by new non-steroidal anti-inflammatory drugs (NSAIDs) such as the diarylheter ocycles celecoxib and rofecoxib. Inhibition occurs by blocking access to th e cyclooxygenase active site where arachidonate is converted to prostagland in G(2) in the biosynthesis of prostaglandins. The diarylheterocycle NSAIDs achieve reversible binding in the entry channel, followed by a stronger bi nding within the active site. The inhibition is nearly irreversible and tim e dependent. We present the results of molecular mechanics modeling of entr y-channel/active-site bindings by celecoxib and rofecoxib to explore the ti me-dependent inhibition process. We find that after the opening of the Arg- 120/Tyr-355 gate to the active site, a series of stronger bindings can occu r, consistent with the onset of time-dependent behavior. We also model hypo thetical bindings of an apparently similar inhibitor, sulindac sulfide, whi ch is known to exhibit reversible, time-independent behavior instead. A rat ionale for the different inhibition behavior is suggested. (C) 2001 Elsevie r Science B.V. All rights reserved.