Study On The Anti-glioblastoma Drugs Based On Microarray And QSAR

Glioblastoma is the common primary malignant tumor which can not be healed via surgical resection.Recently,it is reported that glioma patients treated by surgery combined with drug therapy survive longer.At present,the therapy of the target drug is widely used in clinical practice.Dual target drugs can simultaneously interact with two different targets,which can effectively inhibit tumors via two approaches.The treatment of dual target drug is more effective compared to single target drug.In this work,the different expression genes EGFR and MAD2L1 were selected based on the gene expression profiles from gene expression profiles(Gene Expression Omnibus)database and preliminary validated by real-time fluorescence quantitative PCR.For the design of dual target drugs,the structure-activity relationship of EGFR inhibitors was investigated and Neratinib was selected as EGFR-MAD2L1 dual target drug molecules.The main contribution of this research is as following:I.Microarray data of glioblastoma was collected from GEO database,and the differentially expressed genes(DEGs)of different glioblastoma grades were screened.Then,the feature selection methods including Correlation-based Feature Subset(CFS)and Minimum Redundancy Maximum Relevance(mRMR)were used to further screen DEGs.As a result,19 genes were selected as the DEGs between grade II and grade I;21 genes were selected as the DEGs between grade III and grade II;20 genes were selected as the DEGs between grade IV and grade III.Machine learning algorithm was also applied to contructed prediction models for the different grade glioma,and the prediction accuracy of these models is promising.In addition,GO(Gene Ontology),KEGG(Kyoto Encyclopedia of Genes and Genomes)pathway and PPI(Protein-protein Interaction)analysis of the DEGs were conducted using DAVID,and it was found that genes EGFR and MAD2L1 had an influence on the occurrence of gliomas.We guessed that these genes can be used as potential targets in future study.Finally,it was found that the different expression genes EGFR and MAD2L1 in glioblastoma were overexpression compared to normal bran tissues based on real-time fluorescence quantitative PCR technique.II.100 EGFR inhibitors and 185 non-inhibitors were collected derived from database and literatures.Then,the two-dimension Quantitative Structure-activity Relationship(2D-QSAR)and three-dimension Quantitative Structure-activity Relationship(3D-QSAR)of EGFR inhibitors were studied.30 compounds were designed based on the 3D-QSAR model of EGFR inhibitors,and theses 30 compounds were EGFR inhibitors via screening based on 2D-QSAR model.To further screen the dual target drug molecules,molecular docking method was applied to dock 30 compounds with EGFR and MAD2L1,respectively.Five compounds were selected,and three compounds have been reported.PubChem database was applied to search the existing drugs which have similar structures with these five compounds.We found that the structure of Neratinib and compound C12 was similar.There has been an amount of reports indicating that Neratinib is an inhibitor of EGFR.But the relationship between Neratinib and MAD2L1 has been not reported.The docking result showed that Neratinib could interacte with MAD2L1.We used fluorescence spectroscopy experiment to study the interaction between Neratinib and MAD2L1 and the result showed that Neratinib could interacte with MAD2L1.