Molecular insights into the D1R agonist and D2R/D3R antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations.

(-)-Stepholidine (l-SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have a dual function as a dopamine receptor D1 agonist and D2 antagonist. The preliminary dynamical behaviors of D1R and D2R and their interaction modes with l-SPD were investigated in our previous study. Recently, the pharmacological effect of l-SPD on D3R was elucidated as an antagonist. This new discovery in combination with the explosion of structural biology in GPCR superfamily prompted us to perform a more comprehensive investigation on the special pharmacological profiles of l-SPD on dopamine receptors. In this study, the integration of homology modeling, automated molecular docking, and MD simulations was used to probe the agonistic and antagonistic mechanism of l-SPD on D1R, D2R, and D3R. Our analyses showed that hydrogen bonding of the hydroxyl group on the D ring of l-SPD with side chain of N6.55 which, in combination with hydrophobic stacking between I3.40, F6.44 and W6.48, is the key feature to mediate the agonist effect of l-SPD on D1R, whereas the absence of hydrophobic stacking between I3.40, F6.44, and W6.48 in D2R and D3R excludes receptor activation. Finally, the agonistic and antagonistic mechanisms of l-SPD and an activation model of D1R were proposed on the basis of these findings. The present study could guide future experimental works on these receptors and has the significance to the design of functionally selective drugs targeting dopamine receptors.