Optimization of a small molecule inhibitor of secondary nucleation in a-synuclein aggregation

Parkinson's disease is characterised by the deposition in the brain of amyloid aggregates of & alpha;-synuclein. The surfaces of these amyloid aggregates can catalyse the formation of new aggregates, giving rise to a positive feedback mechanism responsible for the rapid proliferation of & alpha;-synuclein deposits. We report a procedure to enhance the potency of a small molecule to inhibit the aggregate proliferation process using a combination of in silico and in vitro methods. The optimized small molecule shows potency already at a compound:protein stoichiometry of 1:20. These results illustrate a strategy to accelerate the optimisation of small molecules against & alpha;-synuclein aggregation by targeting secondary nucleation.