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One notable phenomenon in the Parkinson's disease (PD) treatment is the identification of inhibitors of the self‐assembly of Alpha‐Synuclein (AS) protein. Here, the interactions of two herbal compounds of Curcumin (CUR) and Rosmarinic‐acid (RA) with the NAC domain of AS were investigated by the molecular dynamics (MD) simulation method. More specifically, the purpose of this study was to investigate the molecular aspects and the inhibition mechanism of the considered molecules, as well as evaluating their effectiveness in preventing the AS aggregation process. The trajectories of MD simulations were used to evaluate the structural properties of the simulated systems and to infer qualitative and quantitative facts regarding the interactions between the considered ligands and the NAC domains. In addition to the MD studies, the energetics of the ligand‐NAC domain interactions were studied by MM‐PBSA method. The free energy of binding and various contributions to it, as modeled in the MM‐PBSA method, were evaluated and analyzed. The results were also analyzed in terms of the rate and strength of ligand binding to the domains. These analyses showed that RA could bind to the NAC domain faster, as compared to CUR, while the latter binds to the domain more strongly than the former does. However, overall, the results imply that both CUR and RA could effectively bind to NAC domains; so, they could be considered as candidates to reduce the aggregation of AS or as potential drugs for PD.

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