基于分子对接柴胡桂枝干姜汤干预初期寒湿郁肺型新型冠状病毒肺炎的活性成分及功效作用机制探讨

Exploring active ingredients and function mechanism of Chaihu Guizhi Ganjiang Decoction against coronavirus disease 2019 based on molecular docking technology

目的预测柴胡桂枝干姜汤干预初期寒湿郁肺型新型冠状病毒肺炎(COVID-19)的药效成分及关键靶标,明确其作用机制。方法查阅文献及临床报道,总结COVID-19中医分期、临床表现及柴胡桂枝干姜汤的功用进行方证关系分析。运用TCMSP数据库筛选柴胡桂枝干姜汤中潜在活性成分及相关靶点,PubMed等数据库筛选肺炎、咳嗽、发热相关靶点,借助Cytoscape软件构建"药物-疾病-靶点"的可视化网络图、蛋白互作网络,并通过STRING数据库进行关键靶点的GO和通路(pathway)富集分析,药效成分采用AutoDock与新型冠状病毒(SARS-CoV-2)3CL水解酶蛋白及血管紧张素转化酶Ⅱ(ACE2)进行分子对接。结果方证关系分析柴胡桂枝干姜汤可奏温阳散寒化湿、兼清郁热、开达膜原之功干预初期寒湿郁肺型COVID-19,通过筛选,预测柴胡桂枝干姜汤中发挥治疗作用主要为156个化学成分作用于159个相关靶点,核心基因有EGFR、TP53、YWHAZ、HSP90AB1、PIK3R1、GRB2等27个,GO和pathway分析柴胡桂枝干姜汤主要参与细胞调节等生物过程及免疫系统相关通路发挥治疗作用,对10个核心成分进行分子对接所得,方中柴胡中柴胡皂苷A、柴胡皂苷D与桂枝中的过氧麦角固醇与SARS-CoV-23CL水解酶蛋白和ACE2有较好的亲和力。结论通过网络药理学与分子对接技术预测柴胡桂枝干姜汤可用于初期寒湿郁肺型COVID-19治疗,方中柴胡、桂枝等中药含有的潜在抗病毒成分可通过调控免疫系统等发挥治疗作用,阐释了中药"多成分-多靶点-多疾病"的作用特点,为临床用药提供理论依据。

Objective To predict the efficacy components and key targets of Chaihu Guizhi Ganjiang Decoction(CGGD)in the intervention of novel coronavirus pneumonia in the cold-dampness obstructing lungs in early stage,and clarify its mechanism.Methods The novel coronavirus pneumonia TCM stage,clinical manifestations and the function of CGGD were analyzed by literature mining and clinical reports.TCMSP database was used to screen potential active components and related targets in CGGD.PubMed database was used to screen pneumonia,cough and fever related targets.With the help of Cytoscape software,a“drug-disease-target”visual network diagram and protein interaction network were constructed,and GO and pathway enrichment analysis of key targets was performed through the STRING database.The active ingredients were molecularly docked with SARS-CoV-23CL hydrolase protein and ACE2 by AutoDock Vina.Results The analysis of the relationship between prescriptions and syndromes showed that CGGD could play warm-yang scattered cold,resolve dampness,clear stagnation and heat,and open up membrane’s power to intervene in early cold-dampness lung type COVID-19.Through screening,the therapeutic effects of CGGD were mainly in 156 chemical components acting on 159 related targets.The core 27 genes predicted and analyzed included EGFR,TP53,YWHAZ,HSP90AB1,PIK3R1,GRB2,etc.GO and pathway analysis showed that CGGD was mainly involved in biological processes such as cell regulation and immune system related pathways to play a therapeutic role.The 10 core components were molecularly docked,saikosaponin A,saikosaponin D,and peroxyergosterol in CGGD had good affinity with 3CL hydrolase protein and ACE2.Conclusion Using network pharmacology and molecular docking technology to predict that CGGD can be used for the treatment of novel coronavirus pneumonia with symptom of cold-dampness obstructing lungs in early stage,potential antiviral ingredients contained in prescription of CGGD,can play a therapeutic role in the treatment of new type of coronavirus pneumonia in the early stage by regulating the immune system.It explains the characteristics of“multi-component-multi-target-multi-disease”of Chinese materia medica,and provides theoretical basis for clinical rational use of medicines.