Molecular studies in understanding Novel Curcumin-Glucoside role in the prevention of Alpha-Synuclein aggregation in relevance to Parkinson's Disease

Background: The synuclein deposition in the brain of Parkinson’s Disease (PD) is the hallmark pathology of the neurodegenerative pathway. The transformation of alpha-synuclein into synuclein monomer, toxic oligomer, and insoluble fibrils are key steps in cell dysfunction. We synthesized a novel molecule, Curcumin-glucoside (Curc-gluc), which has good water solubility and a favorable partition coefficient. Methods: The present study focuses on α-syn aggregation kinetics in the presence and absence of Curc-gluc and Curcumin; we also tested the effect of Copper (Cu) and Iron (Fe) Fe binding through a mathematical approach, biophysical techniques, and docking models. In the mathematical approach, we applied mathematical analyses such as self-association kinetics. In biophysical studies, we used circular dichroism and thioflavin studies. For docking model studies, we employed a two-step computational approach, including ligand pocket analysis and molecular docking simulations. Results: The results indicated that Curc-gluc effectively prevents aggregation better than Curcumin alone and effectively prevents Cu and Fe-induced aggregation of α-syn. Curc-gluc favored α-helix formation and reduced β-formation, thus preventing α-syn aggregation. Docking studies indicated that Curc-gluc derivatives interacted with various chains of α-syn fibrils, namely G-chain, A-chain, I-chain, and E-chain. The interaction data showed that Curcumin Di-Glucoside tetraacetate has the most favorable binding affinity with α-syn fibrils, with -CDOCKER ENERGY of 60.7222 kcal/mol and -CDOCKER INTERACTION ENERGY of 89.6516 kcal/mol. It could form strong hydrogen bond interactions with core functional amino acids such as GLU61, THR72, GLY73, GLU57, THR59, and VAL74. The compounds also exhibit Pi–Pi interaction. Conclusion: These studies indicate the potential of Curc-gluc as a future drug for the clinical management of PD.