Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.
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.
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.
Matthew A
MA
Windsor
Pieter L
PL
Valk
Shu
S
Xu
Surajit
S
Banerjee
Lawrence J
LJ
Marnett
D000818:Animals; D001665:Binding Sites; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation
D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D004008:Diclofenac; D051546:Cyclooxygenase 2; C473384:lumiracoxib
COX-2; Endocannabinoids; Lumiracoxib; Prostaglandins; Substrate-selective inhibition