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

Haixia Ge, Yuemin Bian, Xibing He, Xiang Qun Xie, Junmei Wang

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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 (IC 50 = 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.

Original languageEnglish (US)
Pages (from-to)447-459
Number of pages13
JournalJournal of Computer-Aided Molecular Design
Volume33
Issue number4
DOIs
StatePublished - Apr 15 2019
Externally publishedYes

Keywords

  • Antagonistic activity
  • Dopamine receptors
  • Molecular dynamics simulation
  • Tetrahydroberberrubine

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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