title: Computational insights into function and inhibition of fatty acid amide hydrolase.
abstract: The Fatty Acid Amide Hydrolase (FAAH) enzyme is a membrane-bound serine hydrolase responsible for the deactivating hydrolysis of a family of naturally occurring fatty acid amides. FAAH is a critical enzyme of the endocannabinoid system, being mainly responsible for regulating the level of its main cannabinoid substrate anandamide. For this reason, pharmacological inhibition of FAAH, which increases the level of endogenous anandamide, is a promising strategy to cure a variety of diseases including pain, inflammation, and cancer. Much structural, mutagenesis, and kinetic data on FAAH has been generated over the last couple of decades. This has prompted several informative computational investigations to elucidate, at the atomic-level, mechanistic details on catalysis and inhibition of this pharmaceutically relevant enzyme. Here, we review how these computational studies - based on classical molecular dynamics, full quantum mechanics, and hybrid QM/MM methods - have clarified the binding and reactivity of some relevant substrates and inhibitors of FAAH. We also discuss the experimental implications of these computational insights, which have provided a thoughtful elucidation of the complex physical and chemical steps of the enzymatic mechanism of FAAH. Finally, we discuss how computations have been helpful for building structure-activity relationships of potent FAAH inhibitors.
authors.affiliation: Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy; Laboratory of Computational Chemistry and Biochemistry, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palermo
authors.affiliation: Laboratory of Computational Chemistry and Biochemistry, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rothlisberger
authors.affiliation: Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy. Electronic address: marco.devivo@iit.it.
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D063388:Endocannabinoids / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D053284:Polyunsaturated Alkamides / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide
keywords: FAAH; Molecular dynamics; QM/MM