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 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.
Highlights
The dopaminergic systems in the central nervous system (CNS) have been extensively studied over the past 50 years [1]
In hD2L receptor only the conserved disulfide bridge was modeled, because we considered that a single residue of distance between the two conserved cysteine residues (Cys 399 and Cys 401) may lead to unstable disulfide bond
We have evaluated the similarity of human dopamine D3 (hD3) and hD2L homology models by means of structural alignment
Summary
The dopaminergic systems in the central nervous system (CNS) have been extensively studied over the past 50 years [1]. 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 [2] 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. D2 and D3 receptors share the signal-transduction mechanism, though under certain conditions the latter may exert a weaker stimulation of effectors like AC [7,8] Several pathological conditions such as schizophrenia, Parkinson’s disease, Tourette’s syndrome, and hyperprolactinemia have been linked to a dysregulation of dopaminergic transmission [1]. While D2 receptor is considered the principal target to control the positive symptoms of schizophrenia, none of antipsychotics approved so far discriminates D2 from D3 receptors; on the other hand, the functional significance of D4 receptor largely remains to be defined
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