Computational Study and Modified Design of Selective Dopamine D3 Receptor Agonists

Dopamine D₃ receptor (D₃R) is considered as a potential target for the treatment of nervous system disorders, such as Parkinson's disease. Current research interests primarily focus on the discovery and design of potent D₃ agonists. In this work, we selected 40 D₃R agonists as the research system. Comparative molecular field analysis (CoMFA) of three‐dimensional quantitative structure–activity relationship (3D‐QSAR), structure–selectivity relationship (3D‐QSSR), and molecular docking was performed on D₃ receptor agonists to obtain the details at atomic level. The results indicated that both the CoMFA model (r² = 0.982, q² = 0.503, = 0.893, SEE = 0.057, F = 166.308) for structure–activity and (r² = 0.876, q² = 0.436, = 0.828, F = 52.645) for structure–selectivity have good predictive capabilities. Furthermore, docking studies on three compounds binding to D₃ receptor were performed to analyze the binding modes and interactions. The results elucidate that agonists formed hydrogen bond and hydrophobic interactions with key residues. Finally, we designed six molecules under the guidance of 3D‐QSAR/QSSR models. The activity and selectivity of designed molecules have been improved, and ADMET properties demonstrate they have low probability of hepatotoxicity (<0.5). These results from 3D‐QSAR/QSSR and docking studies have great significance for designing novel dopamine D₃ selective agonists in the future.