Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2)
inhibitors (coxibs) to be approved for use in humans. Within five years after
its release to the public, Vioxx was withdrawn from the market owing to the
adverse cardiovascular effects of the drug. Despite the widespread knowledge of
the development and withdrawal of Vioxx, relatively little is known at the
molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that
the inhibitor contains a methyl sulfone moiety in place of the sulfonamide
moiety found in other coxibs such as celecoxib and valdecoxib. Here, new
crystallization conditions were identified that allowed the structural
determination of human COX-2 in complex with Vioxx and the structure was
subsequently determined to 2.7 Å resolution. The crystal structure provides
the first atomic level details of the binding of Vioxx to COX-2. As anticipated,
Vioxx binds with its methyl sulfone moiety located in the side pocket of the
cyclooxygenase channel, providing support for the isoform selectivity of this
drug.
