Study on the mechanism of Huanglian Jiedu San in treating porcine transmissible gastroenteritis using network pharmacology and molecule docking
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为探究黄连解毒散(HLJDS)治疗猪传染性胃肠炎(TGE)的作用靶点及作用机制,本研究通过中药系统药理学数据库及分析平台(TCMSP)检索HLJDS中的所有化学成分,以口服生物利用度(OB≥30%)、类药性(DL≥0.18)为条件筛选HLJDS的活性化合物及HLJDS活性化合物潜在靶点的数量和名称.利用Gene cards数据库和CTD数据库检索与筛选TGE的相关靶点和HLJDS作用于TGE的相关靶点.采用微生信在线Venn图制作工具分析HLJDS活性化合物和TGE的共同靶点.将上述数据采用Cytoscape 3.9.1软件构建中药-活性化合物-靶点的网络,其中度值>32的化合物可能是关键的化合物或者作用靶点.将HLJDS作用于TGE的相关靶点上传至STRING数据库,获得HLJDS作用于TGE的PPI网络.利用Cytoscape软件中的相关工具分析靶点的网络拓扑学参数,并通过这些参数筛选HLJDS作用于TGE的关键靶点.结果显示,从HLJDS共筛选到77个活性成分和825个药物作用靶点,并筛选到950个TGE相关靶点,其中HLJDS的活性成分与TGE交集的靶点有202个.中药-活性化合物-靶点的网络图结果显示,HLJDS通过77个有效活性化合物作用于202个HLJDS与TGE交集的靶点.PPI网络分析结果显示,肿瘤坏死因子(TNF)、表皮生长因子受体(EGFR)、一氧化氮合酶3(NOS3)、Toll样受体4(TLR4)与信号转导和转录活化因子3(STAT3)等31个靶点可能是HLJDS治疗TGE的关键靶点.通过DAVID数据库对HLJDS作用于TGE的相关靶点进行GO功能分析和KEGG信号通路富集分析.采用Auto Dock Vina 1.1.2将HLJDS度值前6的主要活性化合物PPI网络中前6的关键靶点进行分子对接并获得结合能.将度值前15的HLJDS活性化合物和关键靶点TLR4、TNF-α进行分子对接,通过结合能预测HLJDS活性化合物及对照化合物(姜黄素和维A酸)与TLR4、TNF-α的分子对接效果.GO功能和KEGG信号通路分析结果显示,HLJDS作用于TGE的相关靶点涉及生物过程333个、细胞组分51个、分子功能88个主要功能;涉及AGE-RAGE信号通路、PI3K-Akt信号通路和沙门氏菌感染等与TGE相关的信号通路.分子对接结果显示,HLJDS 6个主要活性化合物与6个关键核心靶点均能够自发结合.且相较于对照化合物姜黄素和维A酸,HLJDS中的黄藤素、黄连素、黄芩素和槲皮素等14个活性化合物与TLR4、TNF-α的结合能更低,结合效果更好.上述结果表明,HLJDS可通过多成分、多靶点、多信号通路作用于TGE的相关靶点,发挥治疗TGE的作用.本研究为HLJDS的进一步开发与应用提供研究基础与方向.
To explore the target and mechanism of Huanglian Jiedu San(HLJDS)in the treatment of porcine transmissible gastroenteritis(TGE),this study obtained the chemical compounds in HLJDS from the traditional Chinese medicine Systems Pharmacology(TCMSP)database,and selected the active compounds with oral bioavailability(OB≥30%)and drug likeness(DL≥0.18).The number and name of potential targets of HLJDS active compounds were also selected and obtained.Gene cards and CTD databases were applied for the screening of related targets of TGE and the targets of HLJDS in the treatment of TGE.The predicted common targets of HLJDS active compounds and TGE were analyzed by Venn Diagram analysis online.From the above data,a network of herbs,active compounds,and common targets was constructed using Cytoscape(v 3.9.1),and the relationships among them were analyzed,in which compounds with degree values>32 may be the key compounds or targets.The potential targets of HLJDS in treating TGE were uploaded to the STRING database to draw a PPI network.Furthermore,the network topology parameters of the targets were analyzed by the relevant tools in Cytoscape software,and the key targets of HLJDS treating on TGE were screened by these parameters.The results showed that a total of 77 active compounds and 825 targets of HLJDS were identified,and 950 targets of TGE were also screened.Among them,202 common targets were obtained between the active compounds of HLJDS and TGE.As shown in the herb-compound-target network,HLJDS acted on the 202 common targets at the intersection of HLJDS and TGE through 77 effective active compounds.The results of PPI network analysis showed that tumor necrosis factor(TNF),epidermal growth factor receptor(EGFR),nitric oxide synthase 3(NOS3),Toll-like receptor 4(TLR4),signal transducer and activator of transcription 3(STAT3)and other 31 targets may be the key targets of HLJDS in the treatment of TGE.In addition,the common targets of HLJDS and TGE were screened out through network pharmacology,and GO function and KEGG signaling pathway enrichment analysis were performed through the DAVID database.From the degree analysis in the network,the top 6 degrees of main active compounds were chosen for molecular docking verification with the top 6 key targets in the PPI network by Auto Dock Vina 1.1.2 to obtain the binding energy.And then,the top 15 degrees of main active compounds were chosen for molecular docking verification with the key targets of TLR4 and TNF-α.The molecular docking effects of active compounds and control compounds(curcumin and retinoic acid)with the targets of TLR4 and TNF-α can be predicted by the binding energy.The targets of HLJDS in treating TGE revealed by GO and KEGG enrichment analysis,which were associated with 333 biological processes,51 cellular components and 88 molecular functions,and the AGE-RAGE signaling pathway,PI3K-Akt signaling pathway,Salmonella infection and other signaling pathways related to TGE.Molecular docking analysis revealed that the 6 main active compounds in HLJDS spontaneously bound to the 6 key targets.Compared with the control compounds curcumin and retinoic acid,the 14 active compounds,such as palmatine,berberine,baicalein and quercetin,had lower binding energy and better binding effects with TLR4 and TNF-α.The results indicated that the potential pharmacological effects of HLJDS in the treatment of TGE were the results of multi-components,multi-targets and multi-signal pathways.This study provides a research basis and direction for the further development and application of HLJDS.
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