Chapter Seven Insights in the Mechanism of Action and Inhibition of N-Acylethanolamine Acid Amidase by Means of Computational Methods

Publication date: 2014 Source:Advances in Protein Chemistry and Structural Biology, Volume 96 Author(s): Alessio Lodola , Silvia Rivara , Marco Mor 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.
Source: Advances in Protein Chemistry and Structural Biology - Category: Biochemistry Source Type: research