基于网络药理学和分子对接技术探讨参附注射液治疗失血性休克的相关机制

Mechanism of Shenfu Injection in the Treatment of Hemorrhagic Shock Based on Network Pharmacology and Molecular Docking Technology

目的:通过网络药理学和分子对接技术探讨参附注射液治疗失血性休克的作用机制。方法:通过中药系统药理学数据库与分析平台获得参附注射液主要成分及作用靶点;检索GeneCards数据库、人类孟德尔遗传综合数据库、治疗靶点数据库和Drugbank数据库获得失血性休克相关靶点;将药物靶点与疾病靶点取交集并绘制韦恩图。将交集靶点上传STRING可视化后得到蛋白质-蛋白质相互作用(PPI)图;利用Cytoscape 3.9.1构建药物-成分-靶点-疾病网络图;使用R 4.2.1软件对靶点进行基因本体(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析;用Pymol 2.4.0、AutoDock Tools 1.5.7软件进行分子对接。结果:参附注射液的2种成分为红参、黑附片提取物,筛选出25个活性成分,并与药物靶点与疾病靶点取交集后得到30个共同靶点,PPI图可见肿瘤坏死因子、胱天蛋白酶(CASP)3、白细胞介素1β、前列腺素内过氧化物合酶(PTGS)2、雌激素受体(ESR)1和CASP8靶点度值较高;参附注射液-有效成分-基因靶点-疾病网络图显示,β-谷甾醇、人参皂苷rh2、德尔妥因、水黄皮素与PTGS2、核受体辅激活蛋白2、PTGS1、肾上腺素受体β2生物学重要性较高;GO功能富集分析主要集中在细胞凋亡、细胞炎症因子的调控;KEGG通路富集分析展示了与失血性休克具有关联的甲型流感等途径。分子对接中,分子间结合能量的变化证实了参附注射液有效成分与失血性休克相关靶点可稳定结合。结论:参附注射液治疗失血性休克具有多成分、多靶点的作用特点,可能与其减少细胞凋亡、抑制炎症发生有关。

OBJECTIVE:To probe into the mechanism of Shenfu injection in the treatment of hemorrhagic shock based on network pharmacology and molecular docking technology.METHODS:The main components and action targets of Shenfu injection were obtained by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.Hemorrhagic shock related targets were obtained by searching the databases of GeneCards,Online Mendelian Inheritance in Man,therapeutic target database and Drugbank.The drug targets and disease targets were intersected and Venn diagram was drawn.The intersection targets were uploaded to STRING for visualization to obtain the protein-protein interaction(PPI)network diagram.Cytoscape 3.9.1 was used to construct the“drug-component-target-disease”network diagram.Gene ontology(GO)functional enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis were performed by using R 4.2.1.Pymol 2.4.0 and AutoDock Tools 1.5.7 were used for molecular docking.RESULTS:The two components of Shenfu injection were ginseng and aconite extract,25 active components were screened,and 30 common targets were obtained after intersected with drug targets and disease targets.The PPI diagram showed that the degree of TNF,CASP3,IL-1β,PTGS2,ESR1 and CASP8 were higher.The network diagram of Shenfu injection-active component-gene target-disease showed that Beta-sitosterol,Ginsenoside rh2,Deltoin,Karanjin and PTGS2,NCOA2,PTGS1,ADRB2 were of high biological importance.GO functional enrichment analysis mainly focused on the regulation of apoptosis and inflammatory factors.KEGG pathway enrichment analysis showed that influenza A and other pathways were associated with hemorrhagic shock.In molecular docking,the change of intermolecular binding energy of molecular docking confirmed that the effective components of Shenfu injection could bind stably to the target related to hemorrhagic shock.CONCLUSIONS:Shenfu injection has the characteristics of multi-components and multi-targets in the treatment of hemorrhagic shock,which may be related to its reduction of cell apoptosis and inhibition of inflammation.