Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor:: Discovery of novel and potent D3 ligands through a hybrid pharmacophore- and structure-based database searching approach

The dopamine 3 (D-3) subtype receptor has been implicated in several neurological conditions, and potent and selective D-3 ligands may have therapeutic potential for the treatment of drug addiction, Parkinson's disease, and schizophrenia. In this paper, we report computational homology modeling of the D-3 receptor based upon the high-resolution X-ray structure of rhodopsin, extensive structural refinement in the presence of explicit lipid bilayer and water environment, and validation of the refined D-3 structural models using experimental data. We further describe the development, validation, and application of a hybrid computational screening approach for the discovery of several classes of novel and potent D-3 ligands. This computational approach employs stepwise pharmacophore and structure-based searching of a large three-dimensional chemical database for the identification of potential D-3 ligands. The obtained hits are then subjected to structural novelty screening, and the most promising compounds are tested in a D-3 binding assay. Using this approach we identified four compounds with K-i values better than 100 nM and eight compounds with K-i values better than 1 muM out of 20 compounds selected for testing in the D-3 receptor binding assay. Our results suggest that the D-3 structural models obtained from this study may be useful for the discovery and design of novel and potent D-3 ligands. Furthermore, the employed hybrid approach may be more effective for lead discovery from a large chemical database than either pharmacophore-based or structure-based database screening alone.