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 diarylheterocycles celecoxib and rofecoxib. Inhibition occurs by blocking access to the cyclooxygenase active site where arachidonate is converted to prostaglandin G(2) in the biosynthesis of prostaglandins. The diarylheterocycle NSAIDs achieve reversible binding in the entry channel, followed by a stronger binding within the active site. The inhibition is nearly irreversible and time dependent. We present the results of molecular mechanics modeling of entry-channel/active-site bindings by celecoxib and rofecoxib to explore the time-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 occur, consistent with the onset of time-dependent behavior. We also model hypothetical bindings of an apparently similar inhibitor, sulindac sulfide, which is known to exhibit reversible, time-independent behavior instead. A rationale for the different inhibition behavior is suggested. (C) 2001 Elsevier Science B.V. All rights reserved.