title: Application of computational methods to the design of fatty acid amide hydrolase (FAAH) inhibitors based on a carbamic template structure.
abstract: Computer-aided approaches are widely used in modern medicinal chemistry to improve the efficiency of the discovery phase. Fatty acid amide hydrolase (FAAH) is a key component of the endocannabinoid system and a potential drug target for several therapeutic applications. During the past decade, different chemical classes of inhibitors, with different mechanisms of action, had been developed. Among them, alkyl carbamic acid biphenyl-3-yl esters represent a prototypical class of active site-directed inhibitors, which allowed detailed pharmacological characterization of FAAH inhibition. Both ligand- and structure-based drug design approaches have been applied to rationalize structure-activity relationships and to drive the optimization of the inhibitory potency for this class of compounds. In this chapter, we review our contribution to the discovery and optimization of therapeutically promising FAAH inhibitors, based on a carbamic template structure, which block FAAH in an irreversible manner exerting analgesic, anti-inflammatory and anxiolytic effects in animal models. The peculiar catalytic mechanism of FAAH, and the covalent interaction with carbamate-based inhibitors, prompted the application of different computer-aided tools, ranging from ligand-based approaches to docking procedures and quantum mechanics/molecular mechanics (QM/MM) hybrid techniques. Latest advancements in the field are also reported.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27/A, Parma, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D004791:Enzyme Inhibitors; D008024:Ligands; D000099252:Fatty Acid Amide Hydrolases