Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents

Abstract

Prostaglandins and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism. Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation. The structure of ovine COX-1 complexed with several NSAIDs has been determined. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.

Substrate access channel topology in membrane-bound prostacyclin synthase

“…These hydrophobic side chains of the putative membraneanchor domains also form an entrance to the substrate-binding channel and potentially form an initial docking site for the lipid substrate, arachidonic acid [9,30]. The topology models developed for PGIS described above have their catalytic domains on the cytoplasmic side of the ER, opposite to the orientation of PGHS, and both of the substrate channels of PGIS and PGHS open to the ER membrane.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…Therapeutic inhibitors tend to exploit this difference in substrate binding sites to ensure selective COX inhibition [106]. Indeed, aspirin and sulindac inhibit both COX-1 and -2, whilst the more recently developed drugs such as celecoxib and rofecoxib (coxibs) target COX-2 selectively, which gives them a better gastrointestinal profile [107,108].…”

Regulation of cyclooxygenase activity by metamizol

“…tures of ovine cyclooxygenase-1 Picot et al, 1994 and Ž . mouse cyclooxygenase-2 Kurumbail et al, 1996 , together with our homology-based models of their human counter-Ž . parts Garcıa-Nieto et al, 1999 , were studied.…”

“…The three-dimensional structures of both Ž enzymes have been solved by X-ray crystallography Picot . et al, 1994;Kurumbail et al, 1996 , and all the residues that make up the cyclooxygenase active site have been shown to be identical except for the amino acid at position 523, which is an isoleucine in cyclooxygenase-1 but a valine in cyclooxygenase-2. This residue is found at the bottom of a hydrophobic channel where nonsteroidal anti-( )Ž .…”