title: Homology modeling of dopamine D2 and D3 receptors: molecular dynamics refinement and docking evaluation.
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.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Chiara Bianca Maria
authors.initials: CB
authors.lastname: Platania
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Leggio
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
mesh_terms: D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000737:chemistry*; D050637:Receptors, Dopamine D3 / Q000737:chemistry*; D012457:Salicylamides / Q000737:chemistry; D040681:Structural Homology, Protein; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D012457:Salicylamides; C045989:eticlopride