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

alpha-Synuclein (alpha-Syn) aggregates are implicated in Parkinson's disease (PD), so inhibitors of alpha-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce alpha-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 alpha-Syn aggregates, we performed a ligand-based virtual screening procedure using two well-known alpha-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 alpha-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 alpha-syn fibrils and a subsequent consensus docking methodology. Overall, this work could furnish new insights in the development of alpha-Syn amyloid inhibitors from synthetic sources.

Automated summary

This study identified a potent α-Syn amyloid formation inhibitor, MeSC-04, through ligand-based virtual screening and investigated its structural requirements. The results demonstrated that MeSC-04 exhibited similar behavior to the known inhibitor SynuClean-D in reducing the number and size of amyloid fibrils. Molecular modeling studies provided insights into the binding mode of MeSC-04 with α-Syn fibrils.