title: Computational Study and Modified Design of Selective Dopamine D3 Receptor Agonists.
abstract: Dopamine D3 receptor (D3 R) 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 D3 R 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 (r(2) = 0.982, q(2) = 0.503, rpred2 = 0.893, SEE  = 0.057, F = 166.308) for structure-activity and (r(2) = 0.876, q(2) = 0.436, rpred2 = 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.
authors: State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing, 100029, China.
authors: Xinli
authors: X
authors: Duan
authors: State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing, 100029, China.
authors: Xin
authors: X
authors: Zhang
authors: State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing, 100029, China.
authors: Binglin
authors: B
authors: Xu
authors: College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
authors: Fang
authors: F
authors: Wang
authors: State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing, 100029, China.
authors: Ming
authors: 0000-0001-5765-9664
authors: M
authors: Lei
mesh_terms: D000978:Antiparkinson Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D019295:Computational Biology; D018491:Dopamine Agonists / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D021621:Imaging, Three-Dimensional; D007700:Kinetics; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000069550:Machine Learning; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D000978:Antiparkinson Agents; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D008024:Ligands; D050637:Receptors, Dopamine D3
keywords: 3D-QSAR; 3D-QSSR; agonist; dopamine D3 receptor; molecular docking