摘要
目的:通过建立雷公藤活性成分-作用靶点、蛋白相互作用、靶点相应的生物功能和通路网络,以及利用分子对接技术探讨雷公藤肾毒性的作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)和毒性与基因比较数据库(CTD)筛选出雷公藤有毒候选化合物。用有机小分子生物活性数据Pub Chem数据库,将所有的候选化合物都转化为标准的Canonical SMILES格式,将SMILES格式文件导入Swiss Target Prediction平台,进行靶点预测,将TCMSP中相应化合物的靶点作为补充,用uniprot将蛋白转换为对应的基因名称,与从人类基因组注释数据库(Gene Cards)中寻找到的肾脏相关基因蛋白进行比对,筛选出重合的蛋白作为雷公藤潜在的肾脏毒性靶点。采用Cytoscape软件构建雷公藤毒性候选成分-作用靶点网络。通过String数据库结合Cytoscape软件绘制蛋白相互作用网络,用DAVID生物信息资源对靶点生物功能及涉及的通路进行分析,最后用Glide软件对关键蛋白与雷公藤毒性候选成分的结合进行验证。结果:雷公藤中筛选得到30种有毒候选成分,涉及209个肾脏毒性作用靶点,网络分析结果表明雷公藤可通过氨基酸代谢、磷脂代谢、儿茶酚胺类物质代谢,抑制肾脏有机阴离子转运体Oatl,Oat2,Oat3的功能,以及诱导凋亡,并参与丝裂原活化蛋白激酶(MAPK)信号通路,JAK/STAT信号通路,血管内皮生长因子(VEGF)信号通路,Toll样受体信号通路,ERBB信号通路,FcεRI信号通路,过氧化物酶体增殖剂激活受体(PPAR)信号通路等对肾脏产生毒性。结论:利用中药多成分-多靶点-多通路的特点,探究了雷公藤肾脏毒性作用机制,为进一步开展雷公藤肾脏毒性作用机制研究提供了新思路和新方法。
Objective: To explore the mechanism of renal toxicity of Tripterygii Radix et Rhizoma by establishing the active component-target,protein interaction,biological function and pathway network corresponding to the target,and using molecular docking technology.Method: The traditional Chinese medicine(TCM)systems pharmacology database(TCMSP) and the comparative toxicogenomics database(CTD) were used to screen The toxic candidate compounds.In PubChem database,convert all candidate compounds into standard Canonical SMILES format,SMILES format file import SwissTargetPrediction platform,target prediction,will be the target of the corresponding compounds in TCMSP supplement with uniprot converts protein antipodal gene name,and from the human genome database(GeneCards) seek to compare the renal related gene protein,overlapping proteins were screened as potential renal toxicity targets of Tripterygii Radix et Rhizoma.Cytoscape software was used to construct the candidate components-target network of Tripterygii Radix et Rhizoma.Cytoscape software was combined with String database to draw the protein interaction network,DAVID platform was used to analyze the biological function of the target and the pathways involved,and Glide software was used to verify the combination of the key protein and the candidate components of tripterygiumwildiitoxicity.Result: The screening of 30 kinds of candidates for toxic ingredients of Tripterygii Radix et Rhizoma,involving 209 renal toxicity targets,network analysis results showed that Tripterygii Radix et Rhizoma by amino acid metabolism,phospholipid metabolism,catecholamine metabolism,inhibiting renal organic anion transporter Oatl,Oat2,Oat3 function,and inducing apoptosis,and participate in the mitogen-activated protein kinase(MAPK) signaling pathways, JAK-STAT signaling pathway,vascular endothelial growth factor(VEGF) signaling pathways,Toll-like receptor signaling pathway, ERBB signaling pathway, FcεRI signaling pathway, peroxisome proliferators-activated receptors(PPAR) signaling pathway such as toxic to the kidneys.Conclusion: The mechanism of kidney toxicity of Tripterygii Radix et Rhizoma was explored by using the characteristics of multi-component,multi-target and multipathway of TCM,which provided new ideas and methods for further research on the mechanism of kidney toxicity of Tripterygii Radix et Rhizoma.
作者
郝俊霞
高梓森
高皓
毕开顺
王健
李佐静
HAO Jun-xia;GAO Zi-sen;GAO Hao;BI Kai-shun;WANG Jian;LI Zuo-jing(School of Pharmacy,School of Pharmaceutical Engineering,School of Medical Devices,Shenyang Pharmaceutical University y Shenyang 110016,China)
出处
《中国实验方剂学杂志》
CAS
CSCD
北大核心
2019年第16期142-151,共10页
Chinese Journal of Experimental Traditional Medical Formulae
基金
国家自然科学基金项目(81303315)
辽宁省自然科学基金项目(20180550342)
关键词
网络药理学
雷公藤
肾脏毒性
通路分析
分子对接
network pharmacology
Tripterygii Radix et Rhizoma
renal toxicity
path analysis
molecular docking
