Diosgenin reduces β-sheet content in mutated α-syn aggregation: Insights from conformational dynamics at intracellular and extracellular neuronal salt concentrations

Parkinson's disease (PD) is marked by the aggregation of α-syn protein and its mutant forms, such as A30P, A53T, and E46K, which make the protein more prone to misfolding and aggregation, leading to neuronal cell death. This study explores the potential of Diosgenin, a phytoconstituent identified through ADMET predictions, to inhibit α-syn aggregation at both extracellular (0.145 M) and intracellular (0.015 M) salt concentrations. Molecular dynamics (MD) simulation revealed that Diosgenin stabilizes α-syn mutants by inducing conformational changes that reduce β-sheet content, a key factor in aggregation. The salt concentration influenced the structural dynamics, with higher salt levels generally promoting more compact and stable conformations. Principal component analysis (PCA) and free energy landscapes further confirmed the enhanced stability of the Diosgenin-bound α-syn mutants. The outcomes of the study suggest that Diosgenin could serve as a promising therapeutic agent for mitigating PD progression by targeting the aggregation of α-syn mutants and reducing its β-sheet content at intracellular and extracellular neuronal salt concentration.