BPS2026 – Computational investigation of the role of the anti-diabetic drug metformin and its analogues in modulating α-synuclein aggregation

Aggregates of α-synuclein (αSyn) are a pathological hallmark of Parkinson’s disease (PD), a neurodegenerative disorder characterized primarily by motor dysfunction. While numerous efforts have focused on preventing αSyn aggregation, a deeper understanding of how small molecules modulate intra- and intermolecular interactions within αSyn remains essential for rational drug design. In this work, we investigate the molecular mechanisms by which the anti-diabetic drug metformin and a series of hydrophobicity-tuned analogues influence the experimentally observed reduction in αSyn aggregation. Using all-atom molecular dynamics simulations combined with replica exchange with solute tempering (REST) for enhanced sampling, we show that variations in hydrophobicity among these positively charged and polar compounds significantly alter αSyn conformational behavior. Our analyses indicate that αSyn-ligand interactions are predominantly governed by electrostatic forces rather than π-π stacking. Comparison of intra-protein contact maps in the presence and absence of ligands reveals specific long-range interactions that are disrupted upon ligand binding, correlating with reduced aggregation propensity. These findings are further validated through REST simulations of αSyn dimers with and without the compounds. For both monomeric and dimeric systems, we also probe the previously proposed “dynamic shuttling” binding mechanism to determine whether ligand-residue interactions occur concurrently or sequentially. Finally, we contrast these results with simulations involving spermine—a highly charged cellular polyamine known to promote αSyn aggregation—to highlight key molecular features that distinguish aggregation inhibitors from promoters. Collectively, our findings provide mechanistic insight into how metformin-like molecules modulate αSyn aggregation and offer valuable guidance for the design of therapeutics targeting synucleinopathies.