Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation |
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Authors: | Laura De Luca,Serena Vittorio,Samuel Peñ a-Dí az,Giovanna Pitasi,Marc Fornt-Suñ é ,Federica Bucolo,Salvador Ventura,Rosaria Gitto |
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Affiliation: | 1.Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D’Alcontres 31, I-98166 Messina, Italy;2.Institut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain;3.Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain;4.ICREA, Passeig Lluis Companys 23, 08010 Barcelona, Spain |
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Abstract: | 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. |
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Keywords: | alpha-synuclein, Parkinson’ s disease, small molecule, virtual screening, binding site prediction, Th-T fluorescence assay |
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