TY - JOUR T1 - High-affinity binding of celastrol to monomeric α-synuclein mitigates in vitro aggregation. JF - J Biomol Struct Dyn Y1 - 2023 A1 - R, Kavya A1 - Aouti, Snehal A1 - Jos, Sneha A1 - Prasad, Thazhe Kootteri A1 - K N, Kumuda A1 - Unni, Sruthi A1 - Padmanabhan, Balasundaram A1 - Kamariah, Neelagandan A1 - Padavattan, Sivaraman A1 - Mythri, Rajeswara Babu AB -

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.

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