基于生物信息学和网络药理学探讨紫草有效成分β,β-二甲基丙烯酰阿卡宁抗结直肠癌作用机制OA

Objective To investigate the function mechanism of anti-colorectal cancer(CRC)effect of the active ingredient β,β-dimethylacryloyl alkannin(DMAS)in Arnebiae Radix using gene expression omnibus(GEO),network pharmacology,and molecular docking.Methods The Swiss Medical Device Database(SwissTargetPrediction),Pharmacophore Matching and Potential Identification Target Platform(Pharmmapper),Human Genome Database(GeneCards),and Compound Target Prediction Database(TargetNet)were used to search for DMAS related targets.Clinically relevant gene analysis was performed using GEO database and weighted gene co-expression network analysis(WGCNA),and the intersection of the two results with the CRC search results in GeneCards database was taken.By utilizing the protein-protein interaction network analysis database(STRING)and Cytoscape software,a protein-protein interaction(PPI)network was created,and key core targets were screened using the Centiscape plugin.To further validate the reliability of these core targets,detailed analysis was conducted using receiver operating characteristic(ROC)curves and they were imported into the Metascape database for Kyoto encyclopedia of genes and genomes(KEGG)pathway and gene ontology(GO)functional enrichment analysis.Finally,AutoDockTools and Pymol software were used to validate and visualize the molecular docking between DMAS and core target proteins.Results A total of 355 DMAS targets were obtained through the database,and 5200 CRC clinical module genes were obtained through WGCNA.Combined with the GeneCards database,totally of 99 DMAS and CRC cross targets were obtained.15 core targets were identified through PPI network analysis.By analyzing the ROC curve,it was determined that serine/threonine kinase(AKT1),protein P53(TP53),β-catenin(CTNNB1),recombinant heat shock protein 90 kDa alpha B1(HSP90AB1),insulin-like growth factor 1(IGF1),tyrosine kinase receptor 2(ERBB2),phosphatase and tensin homolog deleted on chromosome ten(PTEN),cyclin-dependent kinase 2(CDK2),Kirsten rat sarcoma viral oncogene(KRAS),pepsinogen Ⅰ/Ⅱ ratio(PGR),peroxisome proliferator-activated receptor gamma(PPARG),mothers against decapentaplegic homolog 4(SMAD4),cell cycle regulatory protein kinase 4(CDK4),proto-oncogene PIK3CA,and caspase-9(CASP9)were key targets regulated by DMAS for CRC.KEGG and GO enrichment analysis showed that these targets were mainly concentrated in phosphatidylinositol 3-kinase-protein kinase B(PI3K-Akt)signaling pathways.It was further indicated that by the molecular docking results,DMAS could effectively bind to 15 key targets,forming stable protein ligand complexes.Conclusion This study not only reveals the key targets and molecular mechanisms of anti-CRC of DMAS,but also provides a solid theoretical basis for further exploration of the pharmacological mechanisms of anti-CRC of DMAS in the future.