Structural Basis and Mechanism of Chiral Benzedrine Molecules Interacting With Third Dopamine Receptor

In order to investigate the chiral benzedrine molecules corresponding to their different characteristics in biochemical systems, we studied their interaction with D₃R using the docking method, molecular dynamic simulation, and quantum chemistry. The obtained results indicate that the active residues for R‐benzedrine (RAT) bound with D₃R are Ala132, Asp133, and Tyr55, while Asn57, Asp133, Asp168, Cys172, Gly54, Trp24, and Vall136 act as the active residues for S‐benzedrine (SAT). The different active pockets are observed for ART or SAT because they possess different active residues. The binding energies between RAT and SAT with D₃R were determined to be ?44.0 kJ.mol^?1 and ?71.2 kJ.mol^?1, respectively. These results demonstrate that SAT within the studied pocket of D₃R has a stronger capability of binding with D₃R, while it is more feasible for RAT to leave from the interior positions of D₃R. In addition, the results suggest that the D₃R protein can recognize chiral benzedrine molecules and influence their different addictive and pharmacological effects in biochemical systems. Chirality 28:674–685, 2016. © 2016 Wiley Periodicals, Inc.