ABSTRACT ()CStepholidine (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.