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Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib |
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| Authors: | Matthew A. Windsor Pieter L. Valk Shu Xu Surajit Banerjee Lawrence J. Marnett |
| Affiliation: | 1. 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;2. Northeastern Collaborative Access Team, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, United States;3. Argonne National Laboratory, Argonne, IL, 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 2.35 Å crystal structure of lumiracoxib bound to COX-2. |
| Keywords: | COX-2 Substrate-selective inhibition Lumiracoxib Endocannabinoids Prostaglandins |
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