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 (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.
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Acknowledgements
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.
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Ge, H., Bian, Y., He, X. et al. Significantly different effects of tetrahydroberberrubine enantiomers on dopamine D1/D2 receptors revealed by experimental study and integrated in silico simulation. J Comput Aided Mol Des 33, 447–459 (2019). https://doi.org/10.1007/s10822-019-00194-z
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DOI: https://doi.org/10.1007/s10822-019-00194-z