Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation
De Luca, Laura ![Identificador ORCID](/img/uab/orcid.ico)
(University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Vittorio, Serena ![Identificador ORCID](/img/uab/orcid.ico)
(University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Peña Díaz, Samuel ![Identificador ORCID](/img/uab/orcid.ico)
(Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pitasi, Giovanna ![Identificador ORCID](/img/uab/orcid.ico)
(University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Fornt Suñé, Marc ![Identificador ORCID](/img/uab/orcid.ico)
(Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Bucolo, Federica (University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Ventura, Salvador
(Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Gitto, Rosaria
(University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Fecha: |
2022 |
Resumen: |
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. |
Derechos: |
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Lengua: |
Anglès |
Documento: |
Article ; recerca ; Versió publicada |
Materia: |
Alpha-synuclein ;
Parkinson's disease ;
Small molecule ;
Virtual screening ;
Binding site prediction ;
Th-T fluorescence assay |
Publicado en: |
International journal of molecular sciences, Vol. 23, Issue 23 (November 2022) , art. 14844, ISSN 1422-0067 |
DOI: 10.3390/ijms232314844
PMID: 36499173
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Registro creado el 2022-12-20, última modificación el 2024-04-22