Natural compounds extracted from medicinal herbs in the treatment of Parkinson's disease; Molecular Docking, Molecular Dynamics simulation, and Quantum Mechanical calculations.

The dopamine D3 receptor (D3R), which belongs to class A of G-protein-coupled receptors (GPCRs), is a promising target and is significantly involved in the pathology of Parkinson's disease progression. This study examines the inhibitory effects of natural compounds on D3R, highlighting their potential therapeutic applications in mitigating disease progression. Molecular docking simulations were conducted using AutoDock4.2, MOE, ICM, and Vina to evaluate the binding affinity of selected phytochemicals relative to levodopa (compound 1), a standard dopaminergic drug. Compounds such as 5, 13, and 15 demonstrated superior docking scores compared to compound 1. The ADMET analyses revealed favorable bioavailability and drug-likeness profiles, especially for 5, 13, and 15 compounds. Additionally, the stability of the 5_D3R and 13_D3R complexes relative to the 1_D3R complex was confirmed through a molecular dynamics (MD) simulation, which supports the biological potential of polygoni and green tea. According to the binding free energy calculated using MMPB(GB)SA, 5_D3R and 13_D3R complexes exhibit greater stability, which is in agreement with the MD simulation. Finally, a rigorous three-layer ONIOM (M06-2X/6-31G∗:PM6:AMBER) analysis confirmed that compounds 5 and 13 effectively inhibit D3R, highlighting their potential as promising drug candidates.