Homology Modeling of Dopamine D2 and D3 Receptors: Molecular Dynamics Refinement and Docking Evaluation Chiara Bianca Maria Platania, Salvatore Salomone, Gian Marco Leggio, Filippo Drago, Claudio Bucolo* Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy
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 D3 (hD3) receptor has been recently solved. Based on the hD3 receptor crystal structure we generated dopamine D2 and D3 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 hD3 and hD2L receptors was differentiated by means of MD simulations and D3 selective ligands were discriminated, in terms of binding energy, by docking calculation. Robust correlation of computed and experimental Ki was obtained for hD3 and hD2L 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. Citation: Platania CBM, Salomone S, Leggio GM, Drago F, Bucolo C (2012) Homology Modeling of Dopamine D2 and D3 Receptors: Molecular Dynamics Refinement and Docking Evaluation. PLoS ONE 7(9): e44316. doi:10.1371/journal.pone.0044316 Editor: Yang Zhang, University of Michigan, United States of America Received May 25, 2012; Accepted August 1, 2012; Published September 6, 2012 Copyright: ß 2012 Platania et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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. Competing Interests: The authors have declared that no competing interests exist. * E-mail: firstname.lastname@example.org
The dopaminergic systems in the central nervous system (CNS) have been extensively studied over the past 50 years . Dopamine exerts its action through five distinct G-protein coupled receptors (D1–5 receptors), grouped in two classes, D1-like and D2like receptors, that differ in their signal transduction, binding profile and physiological effects . D1-like receptors (D1 and D5) are principally coupled to stimulatory Gs-proteins and enhance the activity of adenylyl cyclase (AC), whereas D2-like receptors (D2, D3, and D4) are primarily coupled to inhibitory Gi-proteins and suppress the activity of AC . Alternative splicing of D2 receptor mRNA leads to generation of two isoforms: D2 short (D2S) and D2 long (D2L), which have been associated (though not exclusively) with presynaptic and postsynaptic populations of D2 receptors, respectively . The difference between these two splicing isoforms is represented by 29 amino acid residues in the III intracellular loop (3ICL), involved in the G protein coupling. The D2S is mainly considered as a presynaptic receptor, whereas, the D2L as a postsynaptic receptor , like the D3 ....
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