Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.
Publication Type:Journal Article
Source:Bioorg Med Chem Lett, Volume 23, Issue 21, p.5860-4 (2013)
Keywords:Animals, Binding Sites, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Diclofenac, Endocannabinoids, Mice, Molecular Docking Simulation
<p>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. </p>