Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates.

Sean Chia, Z Faidon Brotzakis, Robert I Horne, Andrea Possenti, Benedetta Mannini, Rodrigo Cataldi, Magdalena Nowinska, Roxine Staats, Sara Linse, Tuomas PJ Knowles, Johnny Habchi, Michele Vendruscolo

OAI: oai:www.repository.cam.ac.uk:1810/345135 • DOI: 10.17863/CAM.92564

The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson's disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a range of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of α-synuclein oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.

Parkinson’s disease α-synuclein computational docking kinetic-based small-molecule discovery protein aggregation structure-based small-molecule discovery Humans ALPHA-SYNUCLEIN Amyloid Parkinson Disease Kinetics Cell Proliferation Protein Aggregates