Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation
α-Synuclein (α-Syn) aggregates are implicated in Parkinson’s disease (PD), so inhibitors of α-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce α-Syn aggregation in fibrils, thus exerting neuroprotective effects in models of PD. To...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14844 |
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| author | Laura De Luca Serena Vittorio Samuel Peña-Díaz Giovanna Pitasi Marc Fornt-Suñé Federica Bucolo Salvador Ventura Rosaria Gitto |
| author_facet | Laura De Luca Serena Vittorio Samuel Peña-Díaz Giovanna Pitasi Marc Fornt-Suñé Federica Bucolo Salvador Ventura Rosaria Gitto |
| author_sort | Laura De Luca |
| collection | DOAJ |
| description | α-Synuclein (α-Syn) aggregates are implicated in Parkinson’s disease (PD), so inhibitors of α-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce α-Syn aggregation in fibrils, thus exerting neuroprotective effects in models of PD. To expand our knowledge about the structural requirements for blocking the recognition process into the oligomeric assembly of α-Syn aggregates, we performed a ligand-based virtual screening procedure using two well-known α-Syn aggregation inhibitors, SynuClean-D and ZPD-2, as query compounds. A collection of thirty-four compounds bearing distinct chemical functionalities and mutual chemical features were studied in a Th-T fluorescence test, thus identifying 5-(2,6-dinitro-4-(trifluoromethyl)benzyl)-1-methyl-1H-tetrazole (named MeSC-04) as a potent α-Syn amyloid formation inhibitor that demonstrated similar behavior when compared to SynuClean-D in the thioflavin-T-monitored kinetic assays, with both molecules reducing the number and size of amyloid fibrils, as evidenced by electron microscopy. Molecular modeling studies suggested the binding mode of MeSC-04 through the identification of putative druggable pockets on α-syn fibrils and a subsequent consensus docking methodology. Overall, this work could furnish new insights in the development of α-Syn amyloid inhibitors from synthetic sources. |
| first_indexed | 2024-03-09T17:46:17Z |
| format | Article |
| id | doaj.art-360c393d21454b6693a6e9be41c4ca5f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:17Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-360c393d21454b6693a6e9be41c4ca5f2023-11-24T11:08:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231484410.3390/ijms232314844Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid FormationLaura De Luca0Serena Vittorio1Samuel Peña-Díaz2Giovanna Pitasi3Marc Fornt-Suñé4Federica Bucolo5Salvador Ventura6Rosaria Gitto7Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D’Alcontres 31, I-98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D’Alcontres 31, I-98166 Messina, ItalyInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, SpainDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D’Alcontres 31, I-98166 Messina, ItalyInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, SpainDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D’Alcontres 31, I-98166 Messina, ItalyInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, SpainDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D’Alcontres 31, I-98166 Messina, Italyα-Synuclein (α-Syn) aggregates are implicated in Parkinson’s disease (PD), so inhibitors of α-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce α-Syn aggregation in fibrils, thus exerting neuroprotective effects in models of PD. To expand our knowledge about the structural requirements for blocking the recognition process into the oligomeric assembly of α-Syn aggregates, we performed a ligand-based virtual screening procedure using two well-known α-Syn aggregation inhibitors, SynuClean-D and ZPD-2, as query compounds. A collection of thirty-four compounds bearing distinct chemical functionalities and mutual chemical features were studied in a Th-T fluorescence test, thus identifying 5-(2,6-dinitro-4-(trifluoromethyl)benzyl)-1-methyl-1H-tetrazole (named MeSC-04) as a potent α-Syn amyloid formation inhibitor that demonstrated similar behavior when compared to SynuClean-D in the thioflavin-T-monitored kinetic assays, with both molecules reducing the number and size of amyloid fibrils, as evidenced by electron microscopy. Molecular modeling studies suggested the binding mode of MeSC-04 through the identification of putative druggable pockets on α-syn fibrils and a subsequent consensus docking methodology. Overall, this work could furnish new insights in the development of α-Syn amyloid inhibitors from synthetic sources.https://www.mdpi.com/1422-0067/23/23/14844alpha-synucleinParkinson’s diseasesmall moleculevirtual screeningbinding site predictionTh-T fluorescence assay |
| spellingShingle | Laura De Luca Serena Vittorio Samuel Peña-Díaz Giovanna Pitasi Marc Fornt-Suñé Federica Bucolo Salvador Ventura Rosaria Gitto Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation International Journal of Molecular Sciences alpha-synuclein Parkinson’s disease small molecule virtual screening binding site prediction Th-T fluorescence assay |
| title | Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation |
| title_full | Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation |
| title_fullStr | Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation |
| title_full_unstemmed | Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation |
| title_short | Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation |
| title_sort | ligand based discovery of a small molecule as inhibitor of α synuclein amyloid formation |
| topic | alpha-synuclein Parkinson’s disease small molecule virtual screening binding site prediction Th-T fluorescence assay |
| url | https://www.mdpi.com/1422-0067/23/23/14844 |
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