Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study

Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study

Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson'...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Vol. 26; no. 1; p. 78
Main Authors: Jha, Vibhu, Biagi, Marzia, Spinelli, Valeria, Di Stefano, Miriana, Macchia, Marco, Minutolo, Filippo, Granchi, Carlotta, Poli, Giulio, Tuccinardi, Tiziano
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 26-12-2020
MDPI
Subjects:
2-Arachidonoylglycerol
Alzheimer's disease
Binding sites
Breast cancer
Drug development
Endocannabinoid system
Enzymes
hit identification
Inflammation
Inhibitors
Ligands
Lipase
MAGL
Melanoma
Molecular docking
Molecular dynamics
Optimization
Ovarian cancer
Pain
Pharmacology
pharmacophore model
Proteins
Simulation
virtual screening
Workflow
hit identification
pharmacophore model
MAGL
virtual screening
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Summary:Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson's and Alzheimer's disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors.
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ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26010078