文章摘要
马佳文,李想,张翼宙.基于网络药理学与分子对接探究宁心通郁滋肾方治疗早发性卵巢功能不全的作用机制[J].浙江中医药大学学报,2022,46(3):252-263.
基于网络药理学与分子对接探究宁心通郁滋肾方治疗早发性卵巢功能不全的作用机制
Mechanism of Ningxin Tongyu Zishen Formula in Treatment of Premature Ovarian Insufficiency Based on Network Pharmacology and Molecular Docking Technology
DOI：10.16466/j.issn1005-5509.2022.03.005
中文关键词: 宁心通郁滋肾方  早发性卵巢功能不全  四级杆-静电轨道阱高分辨液质联用系统  网络药理学  分子对接  作用机制  槲皮素  信号转导和转录激活因子3
英文关键词: Ningxin Tongyu Zishen Formula  premature ovarian insufficiency  Q Exactive Orbitrap high resolution liquid chromatography coupled with mass spectrometry/mass spectrometry  network pharmacology  molecular docking  mechanism  Quercetin  signal transducer and activator of transcription 3
基金项目:浙江省中医药现代化专项项目(2022ZX011)
作者单位
马佳文 浙江中医药大学　杭州　310053 
李想 浙江中医药大学　杭州　310053 
张翼宙 浙江中医药大学　杭州　310053 
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中文摘要:
      [目的] 基于四级杆-静电轨道阱(Q exactive orbitrap，Q-Orbitrap)高分辨液质联用系统分析结果，利用网络药理学结合分子对接的方法探究宁心通郁滋肾方治疗早发性卵巢功能不全(premature ovarian insufficiency，POI)的作用机制。[方法] 采用Q-Orbitrap高分辨液质联用系统分析宁心通郁滋肾方中的活性成分，再通过Swiss Target Prediction数据库获取方中活性成分的靶点。利用基因组注释数据平台(Genome Annotation Database Platform，GeneCard)和在线人类孟德尔遗传(Online Mendelian Inheritance in Man，OMIM)数据库获取POI的疾病靶点。在String平台构建交集靶点的蛋白互作(protein-protein interaction，PPI)网络后，通过Cytoscape 3.8.2软件筛选关键靶点，并构建“关键靶点-关键活性成分”网络，筛选主要关键活性成分。通过生物学信息注释数据库(the Database for Annotation，Visualization and Integrated Discovery，DAVID)进行基因本体(gene ontology，GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes，KEGG)富集分析。利用Surflex-Dock分子对接程序进行分子对接，获取对接分数(total score)。[结果] 共获得有效活性成分71种，有效活性成分的作用靶点807个，POI疾病靶点1 143个，交集靶点176个。经分析得到信号转导和转录激活因子3(signal transducer and activator of transcription 3，STAT3)、类固醇受体共激活因子(steroid receptor coactivator，SRC)、蛋白激酶 B1(protein kinase B1，AKT1)、90kDa热休克蛋白αA1(heat shock protein 90kDa αA1，HSP90AA1)等39个关键靶点及54种关键活性成分。富集分析结果显示，关键靶点主要涉及凋亡过程的负调控、一氧化氮生物合成过程的正调控、蛋白磷酸化的正调控等生物过程及癌症、癌症中的蛋白聚糖、乙型肝炎等信号通路。分子对接结果提示，槲皮素(Quercetin)作为方中最关键的活性成分与对应关键靶点的对接均较稳定。[结论] 宁心通郁滋肾方可能通过槲皮素、异鼠李素、瑟丹内酯等关键活性成分，作用于STAT3、SRC、AKT1等靶点，通过缓解氧化应激、修复氧化损伤，改善卵巢功能，治疗POI。
英文摘要:
      [Objective] To explore the mechanism of Ningxin Tongyu Zishen Formula in the treatment of premature ovarian insufficiency (POI) using network pharmacology combined with molecular docking based on Q Exactive Orbitrap high resolution liquid chromatography coupled with mass spectrometry/mass spectrometry (Q-Orbitrap LC-MS/MS) system analysis. [Methods] Q-Orbitrap LC-MS/MS was used to analyze the active components in Ningxin Tongyu Zishen Formula， and the targets of the components were obtained by Swiss Target Prediction database. Disease targets of POI were obtained using Genome Annotation Database Platform(GeneCard) and Online Mendelian Inheritance in Man(OMIM) database. After the protein-protein interaction(PPI) network of intersection targets was constructed on String platform， the key targets were screened by Cytoscape 3.8.2 software. Meanwhile， the“key target-key active component” network was constructed to screen the main key active components. The gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis were performed through the DAVID database. The Surflex-dock molecular docking program was used for molecular docking and total scores were obtained. [Results] A total of 71 active components， 807 targets of active components， 1 143 targets of POI and 176 intersection targets were obtained. Thirty-nine key targets including signal transducer and activator of transcription 3(STAT3)， steroid receptor coactivator(SRC)， protein kinase B1(AKT1) and heat shock protein 90kDa αA1(HSP90AA1) and 54 key active components were identified. The enrichment results showed that the key targets were mainly involved in the negative regulation of apoptotic process， positive regulation of nitric oxide biosynthetic process， positive regulation of protein phosphorylation and other biological processes， as well as pathways in cancer， proteoglycan in cancer， hepatitis B and other signaling pathways. The molecular docking results indicated that Quercetin， as the most critical active component of Ningxin Tongyu Zishen Formula， was stable in docking with corresponding key targets.[Conclusion] Ningxin Tongyu Zishen Formula may treat POI through Quercetin， Isorhamnetin， Sedanolide and other key active components acting on key targets， such as STAT3， SRC， AKT1 to improve the ovarian function by alleviating oxidatire stress and repairing oxidative damage.
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