title: Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations.
abstract: (-)-Stepholidine (SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have dual function as a dopamine receptor D1 agonist and D2 antagonist. Insights into dynamical behaviors of D1 and D2 receptors and their interaction modes with SPD are crucial in understanding the structural and functional characteristics of dopamine receptors. In this study a computational approach, integrating protein structure prediction, automated molecular docking, and molecular dynamics simulations were employed to investigate the dual action mechanism of SPD on the D1 and D2 receptors, with the eventual aim to develop new drugs for treating diseases affecting the central nervous system such as schizophrenia. The dynamics simulations revealed the surface features of the electrostatic potentials and the conformational "open-closed" process of the binding entrances of two dopamine receptors. Potential binding conformations of D1 and D2 receptors were obtained, and the D1-SPD and D2-SPD complexes were generated, which are in good agreement with most of experimental data. The D1-SPD structure shows that the K-167_EL-2-E-302_EL-3 (EL-2: extracellular loop 2; EL-3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain and the binding of SPD. Based on our modeling and simulations, we proposed a mechanism of the dual action of SPD and a subsequent signal transduction model. Further mutagenesis and biophysical experiments are needed to test and improve our proposed dual action mechanism of SPD and signal transduction model.
authors.affiliation: Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Jiagao
authors.initials: J
authors.lastname: Cheng
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.forename: James M
authors.initials: JM
authors.lastname: Briggs
authors.forename: Guozhang
authors.initials: G
authors.lastname: Jin
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D003198:Computer Simulation; D004298:Dopamine / Q000737:chemistry; D065127:Dopamine D2 Receptor Antagonists; D021621:Imaging, Three-Dimensional; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010936:Plant Extracts / Q000737:chemistry; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000737:chemistry*; D017448:Receptors, Dopamine D2 / Q000737:chemistry*; D015398:Signal Transduction; D012984:Software; D031607:Stephania / Q000378:metabolism
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D010936:Plant Extracts; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D001599:Berberine; C010513:stepholidine; D004298:Dopamine