Watermelon: setup and validation of an in silico fragment-based approach
We present a new computational approach, named Watermelon, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target’s binding site, utilising molecular fragments as p...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2356179 |
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| author | Miriana Di Stefano Salvatore Galati Lisa Piazza Francesca Gado Carlotta Granchi Marco Macchia Antonio Giordano Tiziano Tuccinardi Giulio Poli |
| author_facet | Miriana Di Stefano Salvatore Galati Lisa Piazza Francesca Gado Carlotta Granchi Marco Macchia Antonio Giordano Tiziano Tuccinardi Giulio Poli |
| author_sort | Miriana Di Stefano |
| collection | DOAJ |
| description | We present a new computational approach, named Watermelon, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target’s binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the Watermelon approach. |
| format | Article |
| id | doaj-art-3961fed658e1472d8c4b064e407e4d66 |
| institution | Kabale University |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-3961fed658e1472d8c4b064e407e4d662024-12-26T09:30:44ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2356179Watermelon: setup and validation of an in silico fragment-based approachMiriana Di Stefano0Salvatore Galati1Lisa Piazza2Francesca Gado3Carlotta Granchi4Marco Macchia5Antonio Giordano6Tiziano Tuccinardi7Giulio Poli8Department of Pharmacy, University of Pisa, Pisa, ItalyDepartment of Pharmacy, University of Pisa, Pisa, ItalyDepartment of Pharmacy, University of Pisa, Pisa, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Milan, ItalyDepartment of Pharmacy, University of Pisa, Pisa, ItalyDepartment of Pharmacy, University of Pisa, Pisa, ItalySbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USADepartment of Pharmacy, University of Pisa, Pisa, ItalyDepartment of Pharmacy, University of Pisa, Pisa, ItalyWe present a new computational approach, named Watermelon, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target’s binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the Watermelon approach.https://www.tandfonline.com/doi/10.1080/14756366.2024.2356179Pharmacophore modeldrug designvirtual screening |
| spellingShingle | Miriana Di Stefano Salvatore Galati Lisa Piazza Francesca Gado Carlotta Granchi Marco Macchia Antonio Giordano Tiziano Tuccinardi Giulio Poli Watermelon: setup and validation of an in silico fragment-based approach Journal of Enzyme Inhibition and Medicinal Chemistry Pharmacophore model drug design virtual screening |
| title | Watermelon: setup and validation of an in silico fragment-based approach |
| title_full | Watermelon: setup and validation of an in silico fragment-based approach |
| title_fullStr | Watermelon: setup and validation of an in silico fragment-based approach |
| title_full_unstemmed | Watermelon: setup and validation of an in silico fragment-based approach |
| title_short | Watermelon: setup and validation of an in silico fragment-based approach |
| title_sort | watermelon setup and validation of an in silico fragment based approach |
| topic | Pharmacophore model drug design virtual screening |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2356179 |
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