Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type
By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking t...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/4/938 |
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| author | Emmanuel Bresso Alessandro Furlan Philippe Noel Vincent Leroux Flavio Maina Rosanna Dono Bernard Maigret |
| author_facet | Emmanuel Bresso Alessandro Furlan Philippe Noel Vincent Leroux Flavio Maina Rosanna Dono Bernard Maigret |
| author_sort | Emmanuel Bresso |
| collection | DOAJ |
| description | By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC<inline-formula> <math display="inline"> <semantics> <msub> <mrow></mrow> <mn>50</mn> </msub> </semantics> </math> </inline-formula> of 7.2 <inline-formula> <math display="inline"> <semantics> <mi mathvariant="sans-serif">μ</mi> </semantics> </math> </inline-formula>M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development. |
| first_indexed | 2024-12-12T21:13:25Z |
| format | Article |
| id | doaj.art-fed9d06eeeda4ee9a2e6bb2818fd9329 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-12T21:13:25Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-fed9d06eeeda4ee9a2e6bb2818fd93292022-12-22T00:11:50ZengMDPI AGMolecules1420-30492020-02-0125493810.3390/molecules25040938molecules25040938Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor TypeEmmanuel Bresso0Alessandro Furlan1Philippe Noel2Vincent Leroux3Flavio Maina4Rosanna Dono5Bernard Maigret6Université de Lorraine, CNRS, Inria, LORIA, F-54000 Nancy, FranceAix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, 13009 Marseille, FranceUniversité de Lorraine, CNRS, Inria, LORIA, F-54000 Nancy, FranceUniversité de Lorraine, CNRS, Inria, LORIA, F-54000 Nancy, FranceAix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, 13009 Marseille, FranceAix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, 13009 Marseille, FranceUniversité de Lorraine, CNRS, Inria, LORIA, F-54000 Nancy, FranceBy using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC<inline-formula> <math display="inline"> <semantics> <msub> <mrow></mrow> <mn>50</mn> </msub> </semantics> </math> </inline-formula> of 7.2 <inline-formula> <math display="inline"> <semantics> <mi mathvariant="sans-serif">μ</mi> </semantics> </math> </inline-formula>M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development.https://www.mdpi.com/1420-3049/25/4/938virtual screeningensemble-dockingstructure-based drug designcross-docking validationinduced fitconformational selectionmet kinase |
| spellingShingle | Emmanuel Bresso Alessandro Furlan Philippe Noel Vincent Leroux Flavio Maina Rosanna Dono Bernard Maigret Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type Molecules virtual screening ensemble-docking structure-based drug design cross-docking validation induced fit conformational selection met kinase |
| title | Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type |
| title_full | Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type |
| title_fullStr | Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type |
| title_full_unstemmed | Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type |
| title_short | Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type |
| title_sort | large scale virtual screening against the met kinase domain identifies a new putative inhibitor type |
| topic | virtual screening ensemble-docking structure-based drug design cross-docking validation induced fit conformational selection met kinase |
| url | https://www.mdpi.com/1420-3049/25/4/938 |
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