Oxicams Bind in a Novel Mode to the Cyclooxygenase Active Site via a Two-water-mediated H-bonding Network
Year: 2014
Type: article
Abstract: Oxicams are widely used nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about the molecular basis of the interaction with their target enzymes, the cyclooxygenases (COX). Isoxicam is a nonselective inhibitor of COX-1 and COX-2 whereas meloxicam displays some selectivity for COX-2. Here we report crystal complexes of COX-2 with isoxicam and meloxicam at 2.0 and 2.45 angstroms, respectively, and a crystal complex of COX-1 with meloxicam at 2.4 angstroms. These structures reveal that the oxicams bind to the active site of COX-2 using a binding pose not seen with other NSAIDs through two highly coordinated water molecules. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding, and the heteroatom of the carboxamide ring of the oxicam scaffold interacts with Tyr-385 and Ser-530 through a highly coordinated water molecule. The nitrogen atom of the thiazine and the oxygen atom of the carboxamide bind to Arg-120 and Tyr-355 via another highly ordered water molecule. The rotation of Leu-531 in the structure opens a novel binding pocket, which is not utilized for the binding of other NSAIDs. In addition, a detailed study of meloxicam·COX-2 interactions revealed that mutation of Val-434 to Ile significantly reduces inhibition by meloxicam due to subtle changes around Phe-518, giving rise to the preferential inhibition of COX-2 over COX-1.
Source: Journal of Biological Chemistry
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G102163711, G107546177, G1313983767, G1509819248, G1664757510, G2164036156, G2287611682, Research Center for Pharmacology and Drug Toxicology, G262962599, G2784524989, Functional Analysis of Cyclooxygenase-2, G3075337988, G3407338877, G409777406, Research Center for Pharmacology & Drug Toxicology, G4883494413, G498139845, G5607048534, G666778509, G6848031779, G6918803902, (R)-flurbiprofen Substrate-Selective Inhibition of COX-2 and Analog Development, G8427536113, NE-CAT Center for Advanced Macromolecular Crystallography, G9000119994, G9000137775, G969889393, G993149817
OpenAlex ID: W2147017754