川乌生物碱类成分致心脏毒性的网络分析与机制预测

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

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STRING数据库构建蛋白-蛋白相互作用网络。通过Metascape数据库进行KEGG通路和GO功能富集分析预测其作用机制。采用AutoDock Vina软件探索关键蛋白与川乌毒性候选成分的亲和力以及结合方式。结果从川乌中共筛选出26个有毒生物碱类成分,涉及33个心脏毒性靶点。基因本体分析和京都基因和基因组百科全书信号通路富集分析结果表明,靶点主要是通过血液循环、跨膜转运参与心脏血液供应和内环境稳态的调节,CHRM2、MAPK14、AGTR2、PARP1等靶点通过调节多种信号通路影响心脏的代谢、发育和形态,进而产生心脏毒性。分子对接结果显示,多数川乌毒性生物碱类成分通过氢键、疏水作用和Pi-Pi键等形式与心脏毒性靶点有强烈的结合活性。结论通过川乌生物碱类成分作用于多个靶点和通路产生心脏毒性的网络分析与机制预测,为后续进一步深入研究川乌心脏毒性作用机制提供新线索。

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.