川乌生物碱类成分致心脏毒性的网络分析与机制预测

目的 运用网络毒理学和分子对接预测川乌生物碱类成分心脏毒性的作用靶点和机制,为其安全用药提供理论指导.方法 检索川乌中有毒生物碱类成分,利用SwissTarget数据库收集成分靶点,用Cytoscape软件构建成分-靶点网络;利用比较毒物遗传学数据库预测心脏毒性靶点,筛选重合靶点作为川乌潜在的心脏毒性靶点,通过STRI...

Network toxicological analysis and mechanism prediction of cardiotoxicity of alkaloids in Aconiti Radix

Objective To explore and predict cardiotoxic targets and mechanism of alkaloids in Aconiti Radix with network toxicology and molecular docking methods,and provide data for the safety of clinical application.Methods Literature related to toxicant alkaloids in Aconiti Radix was retrieved from TCMSP and CTD.SwissTargetPrediction online database was used to screen the target proteins of these ingredients while Cytoscape software was used to construct the toxicant alkaloids-target network.The target proteins of cardiotoxicity were predicted by CTD.The intersection of the two networks was considered to be the potential cardiotoxic targets of Aconiti Radix,which was analyzed to establish the protein-protein interaction(PPI)network by STRING database.The action mechanisms were predicted by Gene Ontology(GO)and the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment with the help of Metascape database.The affinity and binding modes of the key proteins with toxic ingredients of Aconiti Radix were verified by AutoDock Vina software.Results There were 26 candidates for toxicant alkaloids,involving 33 target proteins of cardiotoxicity.The results of GO and KEGG enrichment analyses showed that the targets participated in the supply of blood to the heart and homeostasis of mall molecular substances by means of blood circulation and transmembrane transport.The influence of such targets as CHRM2,MAPK14,AGTR2 and PARP1 on many signaling pathways played an important role in the metabolism,development and form of the heart,and consequently cardiotoxicity occurred.Molecular docking results indicated that the majority of the toxicant alkaloids displayed good binding activities with the cardiotoxic targets,indicateing that hydrogen bonding,hydrophobic effect,and Pi-Pi bonding were the main forms of interactions.Conclusion Based on network pharmacology,it is proved that the interaction of alkaloids in Aconiti Radix with multiple protein targets and pathways results in cardiotoxicity,which can provide new clues to studies on cardiotoxic mechanisms of Aconiti Radix.