Fu Wei, Shen Jianhua, Luo Xiaomin, Zhu Weiliang, Cheng Jiagao, Yu Kunqian, Briggs James M, Jin Guozhang, Chen Kaixian, Jiang Hualiang
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.
Biophys J. 2007 Sep 1;93(5):1431-41. doi: 10.1529/biophysj.106.088500. Epub 2007 Apr 27.
(-)-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.
(-)-千金藤啶碱（SPD）是中药千金藤的一种活性成分，是首个被发现具有多巴胺受体D1激动剂和D2拮抗剂双重功能的化合物。深入了解D1和D2受体的动力学行为及其与SPD的相互作用模式，对于理解多巴胺受体的结构和功能特性至关重要。在本研究中，采用了一种整合蛋白质结构预测、自动分子对接和分子动力学模拟的计算方法，来研究SPD对D1和D2受体的双重作用机制，最终目的是开发用于治疗影响中枢神经系统疾病（如精神分裂症）的新药。动力学模拟揭示了两种多巴胺受体静电势的表面特征以及结合入口的构象“开闭”过程。获得了D1和D2受体的潜在结合构象，并生成了D1-SPD和D2-SPD复合物，这与大多数实验数据高度吻合。D1-SPD结构表明，K-167_EL-2-E-302_EL-3（EL-2：细胞外环2；EL-3：细胞外环3）盐桥对于细胞外结构域的构象变化和SPD的结合都起着重要作用。基于我们的建模和模拟，我们提出了SPD双重作用的机制以及后续的信号转导模型。需要进一步的诱变和生物物理实验来测试和完善我们提出的SPD双重作用机制和信号转导模型。
