Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions

Abstract

Homology model structures of the dopamine D2 receptor (D2R) were generated starting from the active and inactive states of \(\upbeta \)2-adrenergic crystal structure templates. To the best of our knowledge, the active conformation of D2R was modeled for the first time in this study. The homology models are built and refined using MODELLER and ROSETTA programs. Top-ranked models have been validated with ligand docking simulations and in silico Alanine-scanning mutagenesis studies. The derived extra-cellular loop region of the protein models is directed toward the binding site cavity which is often involved in ligand binding. The binding sites of protein models were refined using induced fit docking to enable the side-chain refinement during ligand docking simulations. The derived models were then tested using molecular modeling techniques on several marketed drugs for schizophrenia. Alanine-scanning mutagenesis and molecular docking studies gave similar results for marketed drugs tested. We believe that these new D2 receptor models will be very useful for a better understanding of the mechanisms of action of drugs to be targeted to the binding sites of D2Rs and they will contribute significantly to drug design studies involving G-protein-coupled receptors in the future.

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Acknowledgments

This work was supported by the Max-Planck-Society for Advancement of Science and the “Research Centre Dynamic Systems: Biosystems Engineering (CDS)” funded by the Federal State of Saxony-Anhalt. Part of computations for the work described in this paper was supported by Turkish Scientific and Technical Research Council (TUBITAK) ULAKBIM High Performance Computing Center. S.D. acknowledges support from Bilim Akademisi. The Science Academy, Turkey, under the BAGEP program.

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Correspondence to Matthias Stein or Serdar Durdagi.

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Salmas, R.E., Yurtsever, M., Stein, M. et al. Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions. Mol Divers 19, 321–332 (2015). https://doi.org/10.1007/s11030-015-9569-3

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Keywords

  • G-protein-coupled receptors
  • Dopamine D2 receptor
  • Molecular docking simulations
  • Homology modeling
  • Alanine-scanning mutagenesis