BIOPHYSICAL THEORY AND MODELING |
Dopamine D1 Receptor Agonist and D2 Receptor Antagonist
Effects of the Natural Product (-)-Stepholidine (SPD):
Molecular Modeling and Dynamics Simulations
Wei Fu 1, Jianghua Shen 2, Xiaomin Luo 3, Weiliang Zhu 3, Jiagao Cheng 3, Kunqian Yu 3, James M Briggs 1, Guozhang Jin 3, Kaixian Chen 3 and Hualiang Jiang 3*
1 University of Houston
2 Shanghai Institute of Materia Medica
3 Shanghai institute of Materia Medica
* To whom correspondence should be addressed. E-mail: hljiang{at}mail.shcnc.ac.cn.
Submitted on May 8, 2006
Revised on June 18, 2006
Accepted on 20 March 2007
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Abstract |
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(-)-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 (MD) 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 K167_EL2-E302_EL3 (EL2: extracellular loop 2; EL3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain (ED) 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.
Key Words:
Dopamine receptors, Dual effect of D1 agonist and D2 antagonist, Modeling, Molecular dynamics, Stepholidine
