基于网络药理学的固肠止泻丸治疗肠易激综合征作用机制研究

Pharmacological network-based study on interventional mechanism of Gu-Chang-Zhi-Xie pills for treatment of irritable bowel syndrome

建立"药效成分-疾病靶标-生物学通路"之间的关系,探究固肠止泻丸治疗肠易激综合征(irritable bowel syndrome, IBS)的作用机制。首先,经ADME参数过滤与化学空间主成分分析从固肠止泻丸中筛选出96个活性成分,利用已上市药物在PharmMapper中进行抗IBS疾病靶标预测;其次,采用AutoDock Vina进行活性成分与预测疾病靶标的分子对接验证,建立"药效分子-靶标蛋白"对应关系;然后,利用Cytoscape软件构建"药效成分-疾病靶标"网络模型;最终,借助CluoGO插件将靶标元素映射到KEGG生物学通路中,进一步在通路水平上阐释关键靶标与固肠止泻丸治疗IBS作用机制的潜在联系。预测结果表明,打分靠前的11种关键药效分子大部分属于异喹啉类生物碱,分别主要作用于炎症和痛症两类靶标,对IBS均有不同程度抗炎镇痛的疗效。并且发现关键靶标39个,其中筛选出核心靶标TPH1、TNF-α、IL-6、IFN-γ、MAO-A和IL-10,将靶标映射到KEGG通路29条,其中5-HT信号通路的P值最小,因此推断其药效分子可能主要通过调节5-HT信号合成或转运通路发挥药效作用,并主要作用于6个核心靶标。本研究为进一步开展固肠止泻丸治疗IBS作用机制的研究提供了新思路和新方法。

This study was designed to explore the interventional mechanism involving "multi-components,multi-targets and multi-pathways" of Gu-Chang-Zhi-Xie pills(GCZX) for treatment of irritable bowel syndrome(IBS) using pharmacological network technology. Firstly, 96 active ingredients from GCZX pills were screened by ADME parameter filtration and chemical space principal component analysis, and the targets of anti-IBS function were predicted using PharmMapper online database. Secondly, AutoDock Vina was used to validate the docking between the active ingredients and predicted disease targets, and to establish the corresponding relationship between "pharmacodynamic molecules and target proteins". Finally, the target elements were mapped into the KEGG biological pathway by CluoGO plug-in, which further elucidates the potential relationship between the key targets and the mechanism of action of Gu-Chang-Zhi-Xie pills for treatment of IBS. The results showed that most of the top 11 key pharmacodynamic molecules were isoquinoline alkaloids, which mainly acted on inflammatory or pain targets, with different degrees of anti-inflammatory and analgesic effects. A total of 39 key targets were identified, including TPH1, TNF-α, IL-6, IFN-γ, MAO-A and IL-10. These targets were mapped to 29 KEGG pathways, of which the P-value of 5-HT signaling pathway was the smallest. Therefore, the pharmacodynamic molecules mainly act on 6 core targets and may play a major role in the regulation of 5-HT signal synthesis or transport pathway. This study sets an example for drug development and mechanistic investigation using innovative technology.