TY - JOUR
T1 - Significantly different effects of tetrahydroberberrubine enantiomers on dopamine D1/D2 receptors revealed by experimental study and integrated in silico simulation
AU - Ge, Haixia
AU - Bian, Yuemin
AU - He, Xibing
AU - Xie, Xiang Qun
AU - Wang, Junmei
N1 - Publisher Copyright:
© 2019, Springer Nature Switzerland AG.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Tetrahydroberberrubine (TU), an active tetrahydroprotoberberines (THPBs), is gaining increasing popularity as a potential candidate for treatment of anxiety and depression. One of its two enantiomers, l-TU, has been reported to be an antagonist of both D1 and D2 receptors, but the functional activity of the other enantiomer, d-TU, is still unknown. In this study, experiments were combined with in silico molecular simulations to (1) confirm and discover the functional activities of l-TU and d-TU, and (2) systematically evaluate the molecular mechanisms beyond the experimental observations. l-TU proved to be an antagonist of both D1 and D2 receptors (IC50 = 385 nM and 985 nM, respectively), while d-TU shows no affinity against either D1 or D2 receptor, based on the cAMP assay (D1 receptor) and calcium flux assay (D2 receptor). Results from both flexible-ligand docking studies and molecular dynamic (MD) simulations provided insights at the atomic level. The l-TU-bound structures predicted by MD (1) undergo an outward rotation of the extracellular helical bundles; (2) have an enlarged orthosteric binding pocket; and (3) have a central toggle switch that is prevented from rotating freely. These features are unique to the l-TU enantiomer and provide an explanation for its antagonistic behavior toward both D1 and D2 receptors. The present study provides new sight on the structural and functional relationships of l-TU and d-TU binding to dopamine receptors, and provides guidance to the rational design of novel molecules targeting these two dopamine receptors in the future.
AB - Tetrahydroberberrubine (TU), an active tetrahydroprotoberberines (THPBs), is gaining increasing popularity as a potential candidate for treatment of anxiety and depression. One of its two enantiomers, l-TU, has been reported to be an antagonist of both D1 and D2 receptors, but the functional activity of the other enantiomer, d-TU, is still unknown. In this study, experiments were combined with in silico molecular simulations to (1) confirm and discover the functional activities of l-TU and d-TU, and (2) systematically evaluate the molecular mechanisms beyond the experimental observations. l-TU proved to be an antagonist of both D1 and D2 receptors (IC50 = 385 nM and 985 nM, respectively), while d-TU shows no affinity against either D1 or D2 receptor, based on the cAMP assay (D1 receptor) and calcium flux assay (D2 receptor). Results from both flexible-ligand docking studies and molecular dynamic (MD) simulations provided insights at the atomic level. The l-TU-bound structures predicted by MD (1) undergo an outward rotation of the extracellular helical bundles; (2) have an enlarged orthosteric binding pocket; and (3) have a central toggle switch that is prevented from rotating freely. These features are unique to the l-TU enantiomer and provide an explanation for its antagonistic behavior toward both D1 and D2 receptors. The present study provides new sight on the structural and functional relationships of l-TU and d-TU binding to dopamine receptors, and provides guidance to the rational design of novel molecules targeting these two dopamine receptors in the future.
KW - Antagonistic activity
KW - Dopamine receptors
KW - Molecular dynamics simulation
KW - Tetrahydroberberrubine
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U2 - 10.1007/s10822-019-00194-z
DO - 10.1007/s10822-019-00194-z
M3 - Article
C2 - 30840169
AN - SCOPUS:85062786111
SN - 0920-654X
VL - 33
SP - 447
EP - 459
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 4
ER -