Journal of Computer-Aided Molecular Design

, Volume 33, Issue 4, pp 447–459 | Cite as

Significantly different effects of tetrahydroberberrubine enantiomers on dopamine D1/D2 receptors revealed by experimental study and integrated in silico simulation

  • Haixia GeEmail author
  • Yuemin Bian
  • Xibing He
  • Xiang-Qun XieEmail author
  • Junmei WangEmail author


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.


Tetrahydroberberrubine Dopamine receptors Antagonistic activity Molecular dynamics simulation 



This work was supported by the National Natural Science Foundation of China (NSFC NO. 21302052) and the National Institutes of Health of USA (R01-GM079383, R21-GM097617, P30-DA035778A1). Computational support from the Center for Research Computing of University of Pittsburgh, Pittsburgh Supercomputing Center (CHE180028P) and the Extreme Science and Engineering Discovery Environment (CHE090098, MCB170099 and MCB180045P), is acknowledged.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interest.

Supplementary material

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Supplementary material 1 (DOCX 2728 KB)


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of Life SciencesHuzhou UniversityHuzhouChina
  2. 2.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of PharmacyUniversity of PittsburghPittsburghUSA
  3. 3.NIDA National Center of Excellence for Computational Drug Abuse Research, Drug Discovery InstituteUniversity of PittsburghPittsburghUSA
  4. 4.Department of Computational Biology and Structural Biology, School of MedicineUniversity of PittsburghPittsburghUSA

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