基于系统药理学方法探讨六君子汤治疗胃肠胰神经内分泌肿瘤的作用机制

Exploration of Mechanism of Liujunzi Decoction for the Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms Based on Systematic Pharmacological Methodology

目的建立“药效成分−疾病靶点−生物学通路”之间的关系,探究六君子汤干预胃肠胰神经内分泌肿瘤(Gastroenteropancreatic Neuroendocrine Neoplasms,GEP-NENs)的作用机制。方法经ADME参数过滤与化学空间主成分分析从六君子汤中筛选出154个潜在活性成分,利用已上市用于治疗GEP-NENs的药物在PharmMapper、SwissTargetPrediction中进行GEP-NENs疾病靶点预测;采用Schrödinger软件将筛选出的154个潜在活性成分与预测的疾病靶点进行分子对接研究,从而建立“药效分子−靶点蛋白”对应关系,进而筛选打分靠前的关键药效分子;再利用Cytoscape软件构建“药效成分−疾病靶点”网络模型,借助CluoGO插件将靶点元素映射到KEGG生物学通路中,进一步在通路水平上阐释关键靶点与六君子汤干预GEP-NENs的潜在联系。最终,将主要成分与PCNA、IGF-Ⅱ、MMP2、MMP9、VEGFA等相关靶点进行分子对接,探究六君子汤对GEP-NENs的抑制作用。结果共鉴定六君子汤治疗GEP-NENs候选活性分子27个,治疗靶点32个。KEGG富集分析获得通路95条(P<0.05),主要富集在癌症相关通路。分子对接结果显示,六君子汤通过调控PCNA、MMP2、VEGFA、EGF、KDR等靶点发挥治疗GEP-NENs的作用。结论六君子汤可能通过抑制癌症相关信号通路,调控PCNA、MMP2、VEGFA、EGF、KDR等靶点发挥抗GEP-NENs作用。

Objective To establish the relationship of pharmacodynamic components,disease targets and biological pathways,and to explore the mechanism of Liujunzi Decoction in the intervention of gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs).Methods Firstly,154 potential active ingredients were screened from Liujunzi Decoction by ADME parameter filtration and chemical space principal component analysis,and the GEP NENs disease target prediction was performed by using the listed drugs in PharmMapper and SwissTargetPrediction.Secondly,Schrödinger software was used to conduct molecular docking studies between 154 potential active ingredients and the predicted disease targets,so as to establish the“pharmacodynamic component-target protein”relationship,and then the key pharmacodynamic molecules with high scores were screened.Thirdly,Cytoscape software was used to construct the network model of“pharmacodynamic component-disease target”,and then the CluoGO plug-in was used to map target elements into the KEGG biological pathway to further explain the potential association of key targets with the intervention of GEP-NENs by Liujunzi Decoction at the pathway level.Finally,the main components were docked to PCNA,IGF-Ⅱ,MMP2,MMP9,VEGFA and other related targets to explore the inhibitory effect of Liujunzi Decoction on GEP-NENs.Results A total of 27 candidate active molecules and 32 therapeutic targets of Liujunzi Decoction for the treatment of GEP-NENs were identified.KEGG enrichment analysis obtained 95 pathways(P<0.05),which mainly concentrated in cancer related pathways.Molecular docking results showed that Liujunzi Decoction played a role in treating GEP-NENs by regulating PCNA,MMP2,VEGFA,EGF,KDR and other related targets.Conclusion Liujunzi Decoction played a role in treating GEP-NENs by inhibiting cancer related signal pathways and regulating PCNA,MMP2,VEGFA,EGF,KDR and other related targets.