Homology modeling of dopamine D2 and D3 receptors: molecular dynamics refinement and docking evaluation

PLoS One. 2012;7(9):e44316. doi: 10.1371/journal.pone.0044316. Epub 2012 Sep 6.

Abstract

Dopamine (DA) receptors, a class of G-protein coupled receptors (GPCRs), have been targeted for drug development for the treatment of neurological, psychiatric and ocular disorders. The lack of structural information about GPCRs and their ligand complexes has prompted the development of homology models of these proteins aimed at structure-based drug design. Crystal structure of human dopamine D(3) (hD(3)) receptor has been recently solved. Based on the hD(3) receptor crystal structure we generated dopamine D(2) and D(3) receptor models and refined them with molecular dynamics (MD) protocol. Refined structures, obtained from the MD simulations in membrane environment, were subsequently used in molecular docking studies in order to investigate potential sites of interaction. The structure of hD(3) and hD(2L) receptors was differentiated by means of MD simulations and D(3) selective ligands were discriminated, in terms of binding energy, by docking calculation. Robust correlation of computed and experimental K(i) was obtained for hD(3) and hD(2L) receptor ligands. In conclusion, the present computational approach seems suitable to build and refine structure models of homologous dopamine receptors that may be of value for structure-based drug discovery of selective dopaminergic ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Evaluation, Preclinical
  • Humans
  • Ligands
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / chemistry*
  • Receptors, Dopamine D3 / chemistry*
  • Salicylamides / chemistry
  • Structural Homology, Protein*
  • Thermodynamics
  • User-Computer Interface

Substances

  • Ligands
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Salicylamides
  • eticlopride

Grants and funding

This work was supported in part by a National grant PON01-00110. Dr. Chiara B. M. Platania was supported by the International Ph.D. Program in Neuropharmacology, University of Catania, Italy. The authors wish to thank the “Consorzio Cometa” [http://www.consorzio-cometa.it/] for the computational hours. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.