Structural Investigation of the Dopamine2 Receptor Agonist Bromocriptine Binding to Dimeric D2HighR and D2LowR States [component]

unpublished
The active (D2 High R) and inactive (D2 Low R) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the
more » ... ormational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2 High R active state. There was observed agreement between the calculated and experimentally measured D2 High R selectivity. In the ligand-binding site, the key amino acids identified for the D2 High R were Asp114(3.32) and Glu95(2.65), and for the D2 Low R it was Ser193(5.42). Moreover, replicate MD trajectory analyses demonstrated that the bromocriptine binding site conformational structure was more rigid for the D2 High R state and a more flexible for the D2 Low R state. However, the side chains of the ligand-receptor complex of the D2 High R showed larger variations relative to the corresponding regions of the D2 Low R. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding. 3
doi:10.1021/acs.jcim.7b00722.s001 fatcat:4opqw4argvbetm7ocp4fct5h24