title: Insights in the mechanism of action and inhibition of N-acylethanolamine acid amidase by means of computational methods.
abstract: Computer-aided approaches are widely used in modern medicinal chemistry to improve the efficiency of the discovery phase. N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase belonging to the N-terminal nucleophile (Ntn) hydrolases that primarily degrades anti-inflammatory and analgesic lipid amide palmitoylethanolamide. In this chapter, we review our contribution to (i) the determination of the reaction mechanism of amide hydrolysis catalyzed by cysteine Ntn-hydrolases and (ii) the discovery and optimization of active-site-directed inhibitors of NAAA characterized by a β-lactone warhead. The combination of different computational tools, ranging from homology modeling, docking, and mechanistic simulations based on hybrid quantum mechanics/molecular mechanics potentials, contributed to the elucidation of the mechanism of action and inhibition of NAAA enzyme and to the design of more potent inhibitors.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy. Electronic address: alessio.lodola@unipr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002384:Catalysis; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D004983:Ethanolamines; C022203:N-acylethanolamines; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: (S)-OOPP; CBAH; NAAA; Ntn-hydrolase; PEA; Reaction mechanism; β-Lactone