基于数据库搜寻的5-HT2A受体拮抗剂设计

he serotonin 2A receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of Schizophrenia and depression. In this paper, we reported computational homology modeling of the 5-HT2A receptor 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 antagonistic conformation of 5-HT2A was obtained by the investigation of the interaction mode of 5-HT2A with well-known potent antagonist ketanserin. The active site of the 5-HT2A 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 redundancies, the scoring function was used to rank the hits and docking study was used for the final selection. Finally, 14 molecules were selected and purchased for further biological test.