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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’s an...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794939/ https://www.ncbi.nlm.nih.gov/pubmed/33375358 http://dx.doi.org/10.3390/molecules26010078 |
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author | Jha, Vibhu Biagi, Marzia Spinelli, Valeria Di Stefano, Miriana Macchia, Marco Minutolo, Filippo Granchi, Carlotta Poli, Giulio Tuccinardi, Tiziano |
author_facet | Jha, Vibhu Biagi, Marzia Spinelli, Valeria Di Stefano, Miriana Macchia, Marco Minutolo, Filippo Granchi, Carlotta Poli, Giulio Tuccinardi, Tiziano |
author_sort | Jha, Vibhu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7794939 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77949392021-01-10 Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study Jha, Vibhu Biagi, Marzia Spinelli, Valeria Di Stefano, Miriana Macchia, Marco Minutolo, Filippo Granchi, Carlotta Poli, Giulio Tuccinardi, Tiziano Molecules Article 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. MDPI 2020-12-26 /pmc/articles/PMC7794939/ /pubmed/33375358 http://dx.doi.org/10.3390/molecules26010078 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jha, Vibhu Biagi, Marzia Spinelli, Valeria Di Stefano, Miriana Macchia, Marco Minutolo, Filippo Granchi, Carlotta Poli, Giulio Tuccinardi, Tiziano Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study |
title | Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study |
title_full | Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study |
title_fullStr | Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study |
title_full_unstemmed | Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study |
title_short | Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study |
title_sort | discovery of monoacylglycerol lipase (magl) inhibitors based on a pharmacophore-guided virtual screening study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794939/ https://www.ncbi.nlm.nih.gov/pubmed/33375358 http://dx.doi.org/10.3390/molecules26010078 |
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