基于网络药理学和分子对接技术探讨枳实治疗肝内胆汁淤积的作用机制

中国药物评价 ›› 2023, Vol. 40 ›› Issue (3): 231-239.

基于网络药理学和分子对接技术探讨枳实治疗肝内胆汁淤积的作用机制

陈思琦1，2，郑洋滨1，沈震亚3，陈伟康1*，罗跃华1，2，刘德鸿1

1.江西省药品检验检测研究院，国家药品监督管理局中成药质量评价重点实验室，
江西省药品医疗器械质量工程研究中心，江西南昌 330029；
2.南昌大学药学院，江西南昌 330006； 3.江中药业股份有限公司，江西南昌 330004

收稿日期:2022-08-31 修回日期:2023-03-21 出版日期:2023-06-28 发布日期:2023-07-24
基金资助:
江西省重点研发计划项目（20212BBG73025）；江西省药品监督管理局科研项目（2021KY44）

Study on the Mechanism of Fructus Aurantii Immaturus in Treatment of Intrahepatic Cholestasis Based on Network Pharmacology and Molecular Docking

1.Jiangxi Institute for Drug Control，NMPA Key Laboratory of Quality Evaluation of Traditional Chinese Patent Medicine，
Jiangxi Province Engineering Research Center of Drug and Medical Device Quality， Jiangxi Nanchang 330029， China；
2.School of Pharmacy， Nanchang University， Jiangxi Nanchang 330006，China；
3.Jiangzhong pharmaceutical Co.， Ltd. Jiangxi Nanchang 330004， China

Received:2022-08-31 Revised:2023-03-21 Online:2023-06-28 Published:2023-07-24

摘要/Abstract

摘要： 目的：运用网络药理学和分子对接技术探讨枳实治疗肝内胆汁淤积的有效活性成分及其潜在作用机制，并对枳实黄酮类粗提物治疗胆汁淤积的药效进行验证。方法：从TCMSP数据库和中国知网文献中检索出枳实的有效活性成分并收集其靶点；通过GeneCards和OMIM数据库收集肝内胆汁淤积相关的疾病靶点，将与药物靶点重复的靶点作为潜在靶点，使用 Cytoscape构建“药物-有效成分-靶点-疾病”网络，利用String数据库构建蛋白互作网络（PPI）；借助 Metascape 数据库进行GO富集与KEGG通路富集分析，最后利用AutoDock vina进行分子对接进行初步验证。观察枳实黄酮粗提物对胆汁淤积大鼠谷丙转氨酶（ALT）、谷草转氨酶（AST）、总胆汁酸（TBA）、总胆红素（TBIL）、直接胆红素（DBIL）和碱性磷酸酶（ALP）指标的影响。结果：筛选得到35个活性成分，相关潜在靶点161个，疾病靶点1 248个，枳实治疗肝内胆汁淤积潜在靶点87个，主要作用于AKT1、TP53、TNF、CASP3 、VEGFA、IL6、HIF1A等19个核心靶点，这些共同作用靶点富集于4 405个生物过程和246条信号通路，分子对接结果显示，枳实主要活性成分与核心靶点具有较好的结合活性。药效学验证显示，枳实黄酮提取物高、中剂量组的各生化指标与模型对照组比较，差异有统计学意义（P＜0.05）。结论：枳实治疗肝内胆汁淤积的作用机制具有多成分、多靶点、多通路的特点，且经验证，枳实黄酮粗提物对大鼠胆汁淤积模型有治疗作用，为进一步探究枳实有效成分与体内靶点之间的作用机制奠定了理论基础。

关键词: font-size:medium, ">枳实；肝内胆汁淤积；网络药理学；分子对接；作用机制

Abstract: Objective：To investigate the active ingredients and potential mechanism of Aurantii Fructus Immaturus in the treatment of intrahepatic cholestasis by network pharmacology and molecular docking，andthe efficacy of Aurantii Fructus Immaturus flavone crude extract in the treatment of cholestasis was verified.Methods：The active components were retrieved from TCMSP database and CNKI literature， and their targets were collected. GeneCards and OMIM databases were used to collect disease targets related to intrahepatic cholestasis， and drug targets were identified as potential targets. The "drug-active component-target-disease" network was constructed by Cytoscape， and protein interaction network(PPI) was constructed by String database. Metascape database was used for GO function and KEGG pathway enrichment analysis， and AutoDock vina was used for molecular docking for preliminary verification.The effectswere observed of Aurantii Fructus Immaturus flavone extract on ALT，AST，TBA，TBIL，DBIL，ALP of cholestasis rats.Results：35 active ingredients， 161 related potential targets， 1 248 disease targets and 87 potential targets for intrahepatic cholestasis were screened， mainly acting on 19 core targets including AKT1， TP53， TNF， CASP3， VEGFA， IL6 and HIF1A. These co-acting targets are enriched in 4 405 biological processes and 246 signaling pathways. Molecular docking results showed that Aurantii Fructus Immaturus and core targets has good binding activity. Pharmacodynamic experiment showed that the biochemical indexes of high-dose and medium-dose groups of Aurantii Fructus Immaturus flavone extract were significantly different from those of model control group(P＜0.05). Conclusion：The mechanism of action of Aurantii Fructus Immaturus in the treatment of intrahepatic cholestasis is multi-component， multi-target and multi-pathway， and it was proved that the crude extract of Aurantii Fructus Immaturus flavone extract has therapeutic effect on rat cholestasis model. This study provided a theoretical basis for further research on the mechanism of action between active components of Fructus aurantii and targets in vivo.

Key words: font-size:medium, ">Aurantii Fructus Immaturus； Intrahepatic cholestasis； Network pharmacology；Molecular docking； Action mechanism

中图分类号:

陈思琦, 郑洋滨, 沈震亚, 陈伟康, 罗跃华, 刘德鸿. 基于网络药理学和分子对接技术探讨枳实治疗肝内胆汁淤积的作用机制[J]. 中国药物评价, 2023, 40(3): 231-239.

CHEN Si-qi, ZHENG Yang-bin, SHEN Zhen-ya, CHEN Wei-kang, LUO Yue-hua, LIU De-hong. Study on the Mechanism of Fructus Aurantii Immaturus in Treatment of Intrahepatic Cholestasis Based on Network Pharmacology and Molecular Docking[J]. CHINESE JOURNAL OF DRUG EVALUATION, 2023, 40(3): 231-239.

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