A Pharmacophore Model and Database Searching for Dopamine D2 Receptor Antagonists

• 1、Centre for Molecular Modeling and Design, School of Pharmacy, Fudan University

Abstract：The dopamine D2 receptor (D2R) has been implicated in several neurological conditions and potent D2R antagonists have therapeutic effects in the treatment of schizophrenia and depression. In this paper, we reported computational homology modeling of the D2R based on the high-resolution X-ray structure of β2-adrenergic receptor. The accuracy of the model was validated through Procheck 3.5.4 and AutoDock 4.0 program. The active site of the D2R receptor was mapped by five types of chemical probes by means of grid calculation. The cluster analysis in combination with the available experimental pharmacological data was applied to guide the selection of the pharmacophore feature. Pharmacophore model was built by means of the Catalyst 4.10 and database searching was carried out on Asinex Gold Collection database, which contains ca. 200,000 molecules. As a result, 463 hits were obtained. The Lipinski's Rule of Five was used to filter out the non-drug like molecules, the scoring function was used to rank the hits and docking study was used for the final selection. Finally, 6 molecules were selected and purchased for further biological test.

keywords： pharmacophore model dopamine D2 receptor database search antagonist

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