Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation

Laura De Luca, Serena Vittorio, Samuel Peña-Díaz, Giovanna Pitasi, Marc Fornt-Suñé, Federica Bucolo, Salvador Ventura, Rosaria Gitto*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Article number14844
Number of pages14
JournalInternational journal of molecular sciences
Issue number23
Publication statusPublished - Dec 2022


  • alpha-synuclein
  • binding site prediction
  • Parkinson’s disease
  • small molecule
  • Th-T fluorescence assay
  • virtual screening


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