The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay).The 5-HT2A receptor showed a negatively charged bin-ding pocket.The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure,which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.
When microarray gene expression data are used to predict multiple drug resistance(MDR)phenotypes for anticancer drugs,the normalization strategy and the quality of the selected signature genes are usually the main causes of inconsistency among different experiments.A stable statistical drug response prediction model is urgently required in oncology.In this study,the microarray gene expression data of multiple cancer cell lines with MDR was analyzed.For each probe-set,the expression value was defined as present/absent(1/0)and was classified into a gene set defined with protein domain organization(PDO).After employing the gene content method of phylogenetic analysis,a phylogenetic model(cell tree)for MDR phenotype prediction was built at the PDO gene set level.The results indicate that classification of cancer cell lines is predominantly affected by both the histopa-thological features and the MDR phenotype(paclitaxel and vinblastine).When applying this model to predict the MDR phenotype of independent samples,the phylogenetic model performs better than signature gene models.Although the utility of our procedure is limited due to sample heterogeneity,it still has potential application in MDR research,especially for hematological tumors or established cell lines.
LIU XmYiLI ZuoFengWEN JingRanCAI QingQingXU YeZHANG XiaoYan
