Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

Windsor MA, Valk PL, Xu S, Banerjee S, Marnett LJ
Bioorg Med Chem Lett. 2013 23 (21): 5860-4

PMID: 24060487 · PMCID: PMC3857387 · DOI:10.1016/j.bmcl.2013.08.097

Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to identify the structural determinants of substrate-selective inhibition. The hydrogen-bonding potential of the substituents at the ortho positions of the aniline ring dictated the potency and substrate selectivity of the inhibitors. The presence of a 5'-methyl group on the phenylacetic acid ring increased the potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2) was the most potent and selective inhibitor of endocannabinoid oxygenation. The positioning of critical substituents in the binding site was identified from a 2.35Å crystal structure of lumiracoxib bound to COX-2.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

MeSH Terms (8)

Animals Binding Sites Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Diclofenac Endocannabinoids Mice Molecular Docking Simulation

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