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000829382 1001_ $$0P:(DE-HGF)0$$aPalermo, Giulia$$b0
000829382 245__ $$aThe Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition
000829382 260__ $$aWeinheim [u.a.]$$bWiley-VCH$$c2016
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000829382 520__ $$aThe design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX, that is, a carbamate moiety and the 2-arylpropionic acid functionality, respectively. Molecular modeling and molecular dynamics simulations suggest that ARN2508 uses a noncovalent mechanism of inhibition to block COXs, while inhibiting FAAH via the acetylation of the catalytic Ser241, in line with previous experimental evidence for covalent FAAH inhibition. This study proposes the molecular basis for the dual FAAH/COX inhibition by this novel hybrid scaffold, stimulating further experimental studies and offering new insights for the rational design of novel anti-inflammatory agents that simultaneously act on FAAH and COX.
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000829382 7001_ $$0P:(DE-HGF)0$$aFavia, Angelo D.$$b1
000829382 7001_ $$0P:(DE-HGF)0$$aConvertino, Marino$$b2
000829382 7001_ $$0P:(DE-Juel1)167585$$aDe Vivo, Marco$$b3$$eCorresponding author$$ufzj
000829382 773__ $$0PERI:(DE-600)2209649-8$$a10.1002/cmdc.201500507$$gVol. 11, no. 12, p. 1252 - 1258$$n12$$p1252 - 1258$$tChemMedChem$$v11$$x1860-7179$$y2016
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