High-affinity binding of celastrol to monomeric -synuclein mitigates in vitro aggregation

alpha-Synuclein (alpha Syn) aggregation is associated with Parkinson's disease (PD). The region alpha Syn(36-42) acts as the nucleation 'master controller' and alpha Syn(1-12) as a 'secondary nucleation site'. They drive monomeric alpha Syn to aggregation. Small molecules targeting these motifs are promising for disease-modifying therapy. Using computational techniques, we screened thirty phytochemicals for alpha Syn binding. The top three compounds were experimentally validated for their binding affinity. Amongst them, celastrol showed high binding affinity. NMR analysis confirmed stable alpha Syn-celastrol interactions involving several residues in the N-terminus and NAC regions but not in the C-terminal tail. Importantly, celastrol interacted extensively with the key motifs that drive alpha Syn aggregation. Thioflavin-T assay indicated that celastrol reduced alpha Syn aggregation. Thus, celastrol holds promise as a potent drug candidate for PD. [ GRAPHICS]