Peptide ligand screening of alpha-synuclein aggregation modulators by in silico panning.

Background: alpha-Synuclein is a Parkinson's-disease-related protein. It forms aggregates in vivo, and these aggregates cause cell cytotoxicity. Aggregation inhibitors are expected to reduce alpha-synuclein cytotoxicity, and an aggregation accelerator has recently been reported to reduce alpha-synuclein cytotoxicity. Therefore, amyloid aggregation modulating ligands are expected to serve as therapeutic medicines.

Results: We screened peptide ligands against alpha-synuclein by in silico panning, a method which we have proposed previously. In this study, we selected as the target a very hydrophobic region known as the amyloid-core-forming region. Since this region cannot be dissolved in water, it is difficult to carry out the in vitro screening of its peptide ligand. We carried out 6 rounds of in silico panning using a genetic algorithm and a docking simulation. After the in silico panning, we evaluated the top peptides screened in silico by in vitro assay. These peptides were capable of binding to alpha-synuclein.

Conclusion: We demonstrated that it is possible to screen alpha-synuclein-binding peptides by in silico panning. The screened peptides bind to alpha-synuclein, thus affecting the aggregation of alpha-synuclein.