Inhibition of α-synuclein aggregation by hesperidin as a potent anti-amyloidogenic polyphenol: A computational approach and MM-PBSA /ADMET analysis

A significant part of amyloidogenic illnesses is played by protein misfolding and aggregation caused by intrinsically disordered protein (IDP) self-assembly in Parkinson's disease (PD). In PD, cytotoxic amyloid aggregates of aberrant alpha-synuclein (α-syn) are formed in motor neurons, causing neurodegeneration. Beta-sheet-rich amyloid aggregates are a promising target for mitigating their neurodegenerative consequences. A significant amount of work has been invested in developing chemical compounds that either prevent aggregates from forming or facilitate their breakdown. Finding them might provide a workable strategy for creating a powerful remedy. Several studies indicate that neurological disorders can be treated using small-molecule inhibitors derived from polyphenolic flavonoid compounds. We have thus identified a potential flavonoid molecule that can effectively inhibit the amyloidogenic activity of α-syn through molecular docking and molecular dynamics (MD) simulations. Hesperidin, Morin, and Myricetin were shown to be potential therapeutic leads in the initial screening of flavonoids. Compared to other compounds, the hesperidin-α-Syn combination showed a larger residual energy contribution (ΔE binding -92.69 ± 0.31 kJ mol^-1) and significant binding (6.58 kcal/mol). Secondary structural analysis showed an increased tendency for β-sheets (35 %), with the percentage of β-sheets decreasing in the presence of Hesperidin (29 %). The results showed that Hesperidin binding resulted in a significant reduction in hydrogen bonding between α-syn peptide chains compared to unbound protein. The findings demonstrated that, in contrast to other compounds, Hesperidin alters protein flexibility, hydrophobicity, and structural stability. Therefore, Hesperidin may be a promising treatment option to reduce the negative consequences of PD by efficiently mitigating α-syn amyloid-induced neurotoxicity.