title: Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas.
abstract: Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent inhibition of the fatty acid amide hydrolase (FAAH), which is a promising strategy in the treatment of pain and inflammation. Among the most recent and potent FAAH inhibitors (FAAHi), there are the cyclic piperidine and piperazine aryl ureas. FAAH hydrolyzes efficiently the amide bond of these compounds, forming a covalent enzyme-inhibitor adduct. To rationalize this experimental evidence, we performed an extensive computational analysis centered on piperidine-based PF750 (1) and piperazine-based JNJ1661010 (2), two potent lead compounds used to generate covalent inhibitors as clinical candidates. We found that FAAH induces a distortion of the amide bond of the piperidine and piperazine aryl ureas. Quantum mechanics/molecular mechanics ΔE(LUMO-HOMO) energies indicate that the observed enzyme-induced distortion of the amide bond favors the formation of a covalent FAAH-inhibitor adduct. These findings could help in the rational structure-based design of novel covalent FAAHi.
authors.affiliation: Department of Drug Discovery and Development,  Istituto Italiano di Tecnologia , Via Morego 30, 16163 Genova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palermo
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Matteo
authors.initials: M
authors.lastname: Masetti
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry*; D014867:Water; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D010879:Piperazines; D010880:Piperidines; D014508:Urea; D014867:Water; D000099252:Fatty Acid Amide Hydrolases