基于网络药理学和分子对接技术探讨当归四逆汤治疗系统性硬化症的作用机制

Mechanism of Danggui Sini Decoction in treatment of systemic sclerosis based on network pharmacology and molecular docking

目的 基于网络药理学与分子对接技术探讨当归四逆汤治疗系统性硬化症的作用机制。方法 通过TCMSP数据库检索当归四逆汤中的活性成分并以Swiss Target Prediction数据库预测各活性成分的靶点,采用GeneCards数据库收集系统性硬化症疾病靶点,取其中共同靶点作为潜在的作用靶点并导入String数据库建立蛋白相互作用(PPI)网络,以Cytoscape软件进行网络拓扑分析。将PPI靶点导入DAVID数据库进行基因本体(GO)功能和京都基因组百科全书(KEGG)通路富集分析并以OmicShare平台将结果可视化。构建“通路–靶点”网络并筛选其中关键靶点,并采用CB-Dock平台将作用靶点与活性成分进行分子对接以筛选潜在药效成分。结果 收集得到141个当归四逆汤活性成分及1 047个相关靶点,系统性硬化症疾病靶点1 568个。筛选出潜在作用靶点266个,其中关键靶点6个,分别为蛋白激酶B1(Akt1)、血管内皮生长因子受体2(KDR)、V-Ha-Ras肉瘤病毒癌基因同源物(HRAS)、促分裂原活化蛋白激酶1(MAPK1)、促分裂原活化蛋白激酶3(MAPK3)、血管内皮生长因子A(VEGFA)。主要涉及MAPK信号通路、磷脂酰肌醇3-激酶(PI3K)/Akt信号通路、Rap1信号通路、黏着斑、脂质和动脉粥样硬化、流体剪切应力和动脉粥样硬化等通路的调节。分子对接结果显示,水鬼蕉宾碱、芍药苷、酸枣仁皂苷A等活性成分为治疗中的潜在药效成分。结论 当归四逆汤以多组分、多靶点、多通路干预系统性硬化症,其机制涉及免疫、血管损伤和细胞外基质合成等的调节。

Objective To explore the mechanism of Danggui Sini Decoction in treatment of systemic scleroderma based on network pharmacology and molecular docking method.Method Active substances of Danggui Sini Decoction and related targets were obtained from TCMSP database and Swiss Target Prediction database,the disease targets of systemic scleroderma were acquired from GeneCards database.The intersection targets were selected as potential active targets and import String database to construct PPI network.The network topology analysis was performed by Cytoscape software.The PPI targets were input DAVID database to perform GO and KEGG enrichment analysis and visualized by OmicShare platform.The“targets-pathway”network was construct to screening the key targets.CB-dock platform was utilized to perform the molecular docking between active targets and active substances to screen potential pharmacodynamic components.Results A total of 141 active substances and 1047 related targets were acquired,and 1568diseases targets of systemic scleroderma were obtained.There were 266 potential active targets,including 6 key targets,namely Akt1,KDR,HRAS,MAPK1,MAPK3,and VEGFA.It's mainly involving MAPK signaling pathway,PI3K/Akt signaling pathway,Rap1signaling pathway,focal adhesion,lipid and atherosclerosis and fluid shear stress,and atherosclerosis.Molecular docking results showed that caribine,paeoniflorin,and jujuboside A were potential pharmacodynamic components.Conclusion Danggui Sini Decoction might intervene systemic scleroderma by multi-components,multi-targets,and multi-pathways,the mechanism involves the regulation of immunity,vascular injury,and extracellular matrix synthesis.