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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/1/78 |
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| author | Vibhu Jha Marzia Biagi Valeria Spinelli Miriana Di Stefano Marco Macchia Filippo Minutolo Carlotta Granchi Giulio Poli Tiziano Tuccinardi |
| author_facet | Vibhu Jha Marzia Biagi Valeria Spinelli Miriana Di Stefano Marco Macchia Filippo Minutolo Carlotta Granchi Giulio Poli Tiziano Tuccinardi |
| author_sort | Vibhu Jha |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T13:44:34Z |
| format | Article |
| id | doaj.art-6a42ccaeacba4bd48209567e790759d3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T13:44:34Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6a42ccaeacba4bd48209567e790759d32023-11-21T02:41:22ZengMDPI AGMolecules1420-30492020-12-012617810.3390/molecules26010078Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening StudyVibhu Jha0Marzia Biagi1Valeria Spinelli2Miriana Di Stefano3Marco Macchia4Filippo Minutolo5Carlotta Granchi6Giulio Poli7Tiziano Tuccinardi8Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, ItalyMonoacylglycerol 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.https://www.mdpi.com/1420-3049/26/1/78virtual screeningMAGLpharmacophore modelhit identification |
| spellingShingle | Vibhu Jha Marzia Biagi Valeria Spinelli Miriana Di Stefano Marco Macchia Filippo Minutolo Carlotta Granchi Giulio Poli Tiziano Tuccinardi Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study Molecules virtual screening MAGL pharmacophore model hit identification |
| 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 | virtual screening MAGL pharmacophore model hit identification |
| url | https://www.mdpi.com/1420-3049/26/1/78 |
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