基于网络药理学、分子对接和生物信息学对中药复方抑制COVID-19“细胞因子风暴”分子机制的探索与验证  

Exploration and verification of molecular mechanism of traditional Chinese medicine prescriptions in inhibiting COVID-19 “cytokine storm” based upon network pharmacology,molecular docking and bioinformatics

作　　者：杨莹莹 郭琼琼 唐芳芳 杨玉珍 李林 陈平[2] YANG Ying-ying;GUO Qiong-qiong;TANG Fang-fang;YANG Yu-zhen;LI Lin;CHEN Ping(School of Life Sciences,Zhengzhou Normal University,Henan Zhengzhou 450044,China;School of Basic Medical Sciences,Zhengzhou University,Henan Zhengzhou 450001,China)

机构地区：[1]郑州师范学院生命科学学院,河南郑州450044 [2]郑州大学基础医学院,河南郑州450001

出　　处：《中国医院药学杂志》2021年第2期125-134,共10页Chinese Journal of Hospital Pharmacy

基　　金：河南省重点研发与推广专项(科技攻关)项目(编号:192102310108);河南省青年人才托举工程(编号:2021HYTP040);国家级大学生创新创业训练计划重点项目(编号:202012949005);郑州师范学院大学生科研创新基金项目(编号:2019dc10)。

摘　　要：目的:以确定临床疗效的6种推荐中药复方为研究对象,探索中药治疗COVID-19的分子机制和物质基础。方法:利用TCMSP、IMMPORT、OMIM等数据库获得治疗COVID-19的免疫靶点。Cytoscape3.4.0用于构建"免疫靶点-中药-化合物-疾病"网络以及网络拓扑学分析,随后进行PPI、GO功能和KEGG通路富集分析。AutoDock Vina用于分子对接。SsGSEA利用转录组和microarray数据计算免疫细胞浸润程度。结果:对"免疫靶点-中药-化合物-疾病"网络进行拓扑学分析,本研究发现28种COVID-19免疫靶点高度关联化合物,对其进行分子对接发现豆甾醇、靛玉红、黄芩素等与血管紧张素转化酶Ⅱ(ACE2,angiotensin converting enzymeⅡ)以及新型冠状病毒(SARS-CoV-2)3CL水解酶具有较好的结合活性。6种复方均通过TNF、IL^(-1)7等信号通路发挥抗炎、调节细胞因子活性。IL-6是6种复方抗COVID-19的共同核心免疫靶标。肺组织表达谱生物信息学分析证实IL-6的表达与活化CD8+T细胞、调节T细胞等免疫细胞的浸润高度有关,是免疫反应的关键分子。结论:中药复方的活性化合物豆甾醇、靛玉红、黄芩素等作用于IL-6、IL^(-1)0、IL^(-1)B等免疫靶点调节TNF、IL^(-1)7等多条信号通路,从而发挥抑制COVID-19"细胞因子风暴"的作用。OBJECTIVE Six recommended TCM(traditional Chinese medicine)prescriptions with confirmed clinical efficacy were adopted as the research objects for exploring the molecular mechanism and material basis of TCM prescriptions in the treatment of COVID-19. METHODS TCMSP,IMMPORT,OMIM and other databases were accessed for obtaining immune targets related to COVID-19.The "immune targets-herb-compound-disease" network was constructed by Cytoscape-3.4.0 and followed by PPI,GO and KEGG pathway enrichment analysis.Molecular docking was performed by AutoDock Vina software.Transcriptome and microarray data were utilized by ssGSEA for calculating the relative level of immune cell infiltration. RESULTS Based upon the topological analysis of "immune targets-herb-compound-disease" network,28 highly correlated compounds of COVID-19 immune targets were identified and molecular docking revealed that the compounds of stigmasterol,indirubin and baicalein had excellent binding activities with angiotensin converting enzyme II(ACE2)and novel coronavirus(SARS-COV-2)3 CL hydrolase.All six TCM prescriptions demonstrated anti-inflammatory and regulatory cytokine activities through TNF and IL^(-1)7 signaling pathways.IL-6 was a common core immune target of six TCM prescriptions for inhibiting COVID-19.Bioinformatic analysis of expression profile of lung tissues confirmed that IL-6 expression was highly correlated with the activation of CD8+T cells,regulation of T cells and other immune cells as the key molecule of immune response. CONCLUSION The active compounds of stigmasterol,indirubin and baicalein in TCM may act on IL-6,IL^(-1)0,IL^(-1) B and other immune targets to regulate multiple signaling pathways such as TNF and IL^(-1)7 for inhibiting "cytokine storm" of COVID-19.

关 键 词：COVID-19 中药复方 网络药理学 分子对接 细胞因子风暴 

分 类 号：R285[医药卫生—中药学]