Abstract
Monoacylglycerol lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The identification of reversible MAGL inhibitors, devoid of the side effects associated to prolonged MAGL inactivation, is a hot topic in medicinal chemistry. In this study, a novel phenyl(piperazin-1-yl)methanone inhibitor of MAGL was identified through a virtual screening protocol based on a fingerprint-driven consensus docking (CD) approach. Molecular modeling and preliminary structure-based hit optimization studies allowed the discovery of derivative 4, which showed an efficient reversible MAGL inhibition (IC50 = 6.1 µM) and a promising antiproliferative activity on breast and ovarian cancer cell lines (IC50 of 31–72 µM), thus representing a lead for the development of new and more potent reversible MAGL inhibitors. Moreover, the obtained results confirmed the reliability of the fingerprint-driven CD approach herein developed.
Highlights
The endocannabinoid system (ECS) is constituted by the cannabinoid receptors type 1 and type 2 (CB1, CB2), a series of signalling molecules called endocannabinoids and biosynthetic and degrading enzymes involved in the production and transformation of the eCBs
AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) to arachidonic acid and ethanolamine, whereas 2-AG is predominantly hydrolyzed to arachidonic acid and glycerol by monoacylglycerol lipase (MAGL) and to a lesser extent by a/b hydrolase-6 and -12 (ABHD6 and ABHD12)
We decided to develop a virtual screening (VS) protocol based on a fingerprintdriven consensus docking (CD) approach, in order to identify novel compounds endowed with MAGL inhibitory activity
Summary
Supplemental data for this article can be accessed here. ß 2019 The Author(s). Central residues A51 and M123 form two H-bonds with the carbonyl group of the ligand and all surrounding residues show lipophilic interactions with the inhibitor. On the basis of the symmetrical features of MAGL binding site, the CD approach might lead to a high number of false negatives, since only compounds showing a unique preferred binding orientation are proposed as potential active ligands. We decided to develop a VS protocol based on a fingerprintdriven CD approach, in order to identify novel compounds endowed with MAGL inhibitory activity
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