Canna~Fangled Abstracts

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

By September 27, 2013 No Comments
[Epub ahead of print]

pm2Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

Source

A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Department of Chemistry, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States.

Abstract

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.

KEYWORDS:

COX-2, Endocannabinoids, Lumiracoxib, Prostaglandins, Substrate-selective inhibition

PMID:

 

24060487

 

[PubMed – as supplied by publisher]
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