基于网络药理学和分子对接探究黄芪桂枝五物汤干预紫杉醇诱导周围神经毒性的作用机制

Exploring Mechanism of Huangqi Guizhi Wuwu Decoction(黄芪桂枝五物汤)in Intervening Paclitaxel-Induced Peripheral Neurotoxicity Based on Network Pharmacology and Molecular Docking

目的使用网络药理学的方法探究黄芪桂枝五物汤干预紫杉醇诱导的周围神经毒性的机制。方法通过中药系统药理学数据库和分析平台(Traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)获得黄芪桂枝五物汤的有效活性成分及其作用靶点,汇总DrugBank数据库、OMIM(Online Mendelian Inheritance in Man,OMIM)数据库、PharmGkb(PharmacogenomicsKnowledgebase,PharmGkb)数据库、TTD(Therapeutic Target Database,TTD)数据库、GeneCards数据库中有关紫杉醇诱导周围神经毒性的相关疾病靶点,Cytoscape 3.7.2用于构建复方有效成分—靶点网络,将作用靶点导入String数据库构建PPI(Protein-protein interaction,PPI)蛋白互作网络,再通过DAVID(Database for Annotation,Visualization and Integrated Discovery,DAVID)数据库进行GO、KEGG富集,最后进行分子对接验证。结果获得了黄芪桂枝五物汤中有效活性成分74个,干预神经毒性的潜在靶点76个,复方有效活性成分—作用靶点网络显示槲皮素、豆甾醇、β-谷甾醇等与靶点具有较多的对应关系,TP53、AK1、JUN是蛋白互作网络中degree值较高的蛋白,GO富集与KEGG富集显示细胞对氧化应激的反应、膜筏、结合DNA转录因子、铂耐药是复方干预神经毒性的主要途径。PPI中关键靶点蛋白与活性成分的分子对接结果良好。结论初步研究了黄芪桂枝五物汤干预紫杉醇周围神经毒性的作用机制,探明了黄芪桂枝五物汤可以通过多个靶点、多条通路来发挥干预紫杉醇周围神经毒性的作用。

Objective To explore the mechanisms of Huangqi Guizhi Wuwu Decoction(黄芪桂枝五物汤)intervening in pa⁃clitaxel-induced peripheral neurotoxicity by using a network pharmacology approach.Methods The effective active components and targets of Huangqi Guizhi Wuwu Decoction were obtained the traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP).The related disease targets of paclitaxel-induced peripheral neurotoxicity in DrugBank,Online Mendelian Inheritance in Man(OMIM),Pharmacogenomics Knowledgebase(PharmGkb),Therapeutic Target Database(TTD)and GeneCards were summarized.Cytoscape 3.7.2 was used to construct compound effective component-target network.The protein-protein interaction(PPI)protein interaction network was constructed by importing the target into the string database,and then GO and KEGG enrichment analyses were performed through the database for annotation,visualization and integrated discov⁃ery(DAVID),and finally the molecular docking verification was performed.Results A total of 74 active ingredients and 76 poten⁃tial targets were obtained for intervention in neurotoxicity in Huangqi Guizhi Wuwu Decoction.The active ingredient-target net⁃work of the compound showed that quercetin,dousterol andβ-sitosterol had more correspondence with the targets.TP53,AK1 and JUN were the proteins with high degree values in the protein interactions network.GO enrichment and KEGG enrichment an⁃alyses showed that cellular responses to oxidative stress,membrane rafts,binding of DNA transcription factors and platinum resist⁃ance were the main pathways of compounded interventions in neurotoxicity.The molecular docking of key target proteins in PPI with the active ingredient turned out to be good.Conclusion Preliminary study on the mechanism of Huangqi Guizhi Wuwu De⁃coction on the peripheral neurotoxicity of paclitaxel showed that Huangqi Guizhi Wuwu Decoction could play a role in intervening the peripheral neurotoxicity of paclitaxel through multiple targets and multiple pathways.