TitleHigh-affinity binding of celastrol to monomeric α-synuclein mitigates in vitro aggregation.
Publication TypeJournal Article
Year of Publication2023
AuthorsR K, Aouti S, Jos S, Prasad TKootteri, N KK, Unni S, Padmanabhan B, Kamariah N, Padavattan S, Mythri RBabu
JournalJ Biomol Struct Dyn
Date Published2023 Feb 06

α-Synuclein (αSyn) aggregation is associated with Parkinson's disease (PD). The region αSyn acts as the nucleation 'master controller' and αSyn as a 'secondary nucleation site'. They drive monomeric αSyn to aggregation. Small molecules targeting these motifs are promising for disease-modifying therapy. Using computational techniques, we screened thirty phytochemicals for αSyn binding. The top three compounds were experimentally validated for their binding affinity. Amongst them, celastrol showed high binding affinity. NMR analysis confirmed stable αSyn-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 αSyn aggregation. Thioflavin-T assay indicated that celastrol reduced αSyn aggregation. Thus, celastrol holds promise as a potent drug candidate for PD.Communicated by Ramaswamy H. Sarma.

Alternate JournalJ Biomol Struct Dyn
PubMed ID36744543