Title : Crystal structure of rofecoxib bound to human
cyclooxygenase-2
Abstract :
- 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- Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug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