title: The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition.
abstract: The 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.
authors.affiliation: Laboratory of Molecular Modeling & Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palermo
authors.affiliation: Laboratory of Molecular Modeling & Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Angelo D
authors.initials: AD
authors.lastname: Favia
authors.affiliation: Laboratory of Molecular Modeling & Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy.
authors.forename: Marino
authors.initials: M
authors.lastname: Convertino
authors.affiliation: Laboratory of Molecular Modeling & Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genoa, Italy. marco.devivo@iit.it.|Computational Biomedicine (IAS-5/INM-9), Forschungszentrum Jülich, Wilhelm-Johnen-Straße, 52428, Jülich, Germany. marco.devivo@iit.it.
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D048448:Phenylcarbamates / Q000737:chemistry / Q000378:metabolism; D010666:Phenylpropionates / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D008024:Ligands; D048448:Phenylcarbamates; D010666:Phenylpropionates; D000099252:Fatty Acid Amide Hydrolases; C000600450:ARN2508
keywords: cyclooxygenase; drug design; fatty acid amide hydrolase; molecular dynamics; molecular modeling; multitarget ligands