Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

• DOI: 10.1073/pnas.0909765106
• Publication Date: 2009-12-02T02:54:06Z
• Authors: Gilad Rimon; Ranjinder S. Sidhu; D. Adam Lauver; Jullia Y. Lee; Narayan P. Sharma; Chong Yuan; Ryan A. Frieler; Raymond C. Trievel; Benedict R. Lucchesi; William L. Smith
• Keywords: Celecoxib; Thromboxane B2

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A 2 formed by platelets AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas activity is preferentially blocked inhibitors called coxibs. COXs homodimers composed identical subunits, but we have shown that only one subunit active at a time during catalysis; moreover, many nsNSAIDS bind to single COX dimer inhibit the entire dimer. Here, report surprising observation celecoxib other coxibs tightly COX-1. Although binding monomer does not affect normal catalytic processing second, partner subunit, interfere inhibition in vitro. X-ray crystallographic results obtained celecoxib/COX-1 complex show how can two available sites Finally, find administration dogs interferes ability low dose AA-induced ex vivo platelet aggregation. such as widely used for pain relief. Because exhibit cardiovascular side effects, they often prescribed combination low-dose prevent Our studies predict cardioprotective effect on may be blunted when taken