基于网络药理学研究金银花干预心力衰竭的作用机制

STUDY ON THE MECHANISM OF LONICERAE JAPONICAE INTERVENTION IN HEART FAILURE BASED ON NETWORK PHARMACOLOGY

目的运用网络药理学方法研究金银花干预心力衰竭的主要活性成分及潜在靶点,探讨金银花干预心力衰竭的作用机制。方法利用TCMSP数据库检索金银花中的化合物,口服生物利用度(OB)≥30%和类药性(DL)≥0.18作为筛选金银花活性成分的标准。在Genecards数据库和OMIM数据库中输入关键词“Heart Failure”,筛选心力衰竭相关靶点。将金银花作用的靶点与心力衰竭相关的靶点取交集,得到金银花干预心力衰竭的靶点。通过STRING数据库构建交集基因的蛋白互作网络(PPI),应用Cytoscape3.8.2软件分析PPI网络中核心靶点,然后进行基因GO功能和KEGG通路富集分析,构建“成分-靶点-通路”网络。使用Autodock Vina 1.2.0、Discovery Studio 2021、PyMol 2.2进行分子对接,验证网络药理学分析结果。结果检索TCMSP数据库得到金银花的23个化学活性成分,213个与心力衰竭相关的作用靶点。经GO功能和KEGG通路富集分析显示,金银花主要参与癌症通路、内分泌抵抗等多种生物途径,主要涉及PI3K-Akt信号通路、cAMP信号通路、TNF信号通路等。通过构建“药物成分-靶点-通路”网络,显示金银花干预心力衰竭的主要成分是JYH12(secologanicdibutylacetal_qt,环有机二丁基缩醛_qt)、JYH23(dinethylsecologanoside,二乙基芥子油苷),排名较高的靶点有AKT1、PIK3R1、PIK3CA。通过分子对接显示JYH12、JYH23与AKT1、PIK3R1结合活性较好。结论金银花的主要活性成分JYH12、JYH23可能是通过参与调节AKT1、PIK3R1基因,干预PI3K-Akt、cAMP、TNF等信号通路实现多靶点、多通路干预心力衰竭。

Objective The main active components and potential targets of Flos Lonicerae in the intervention of heart failure were studied by means of network pharmacology to explore the mechanism of Flos Lonicerae in the intervention of heart failure.Methods Using the TCMSP database to search for compounds in honeysuckle,oral bioavailability(OB)≥30%and drug-like properties(DL)≥0.18 were used as the criteria for screening the active components of honeysuckle.Enter the keyword"Heart Failure"in the Genecards database and the OMIM database to screen heart failure-related targets.The target of honeysuckle action and heart failure-related targets were intersected to obtain the target of honeysuckle intervening in heart failure.The protein interaction network(PPI)of intersecting genes was constructed through the STRING database,the core targets in the PPI network were analyzed by Cytoscape 3.8.2 software,and then the gene GO function and KEGG pathway enrichment analysis were performed to construct a"component-target-pathway"network.Molecular docking was performed using Autodock Vina 1.2.0,Discovery Studio 2021,and PyMol 2.2 to verify the results of network pharmacology analysis.Results The TCMSP database was searched to obtain 23 chemically active components of honeysuckle and 213 targets related to heart failure.The GO function and KEGG pathway enrichment analysis showed that honeysuckle is mainly involved in cancer pathways,endocrine resistance and other biological pathways,mainly involving PI3K-Akt signaling pathway,cAMP signaling pathway,TNF signaling pathway,etc.Through the construction of the"drug component target pathway"network,it is shown that the main components of honeysuckle in the intervention of heart failure are JYH12(secologically dibutyl acetal_qt,cyclic organic dibutyl acetal_qt),JYH23(diethyl glucoside,diethyl mustard),and the higher ranked targets are AKT1,PIK3R1,and PIK3CA.Molecular docking showed that JYH12 and JYH23 had better binding activities to AKT1 and PIK3R1.Conclusions JYH12 and JYH23,the main active components of honeysuckle,may be involved in regulating AKT1 and PIK3R1 genes and interfering with PI3K Akt,cAMP,TNF and other signal pathways to achieve multi target and multi pathway intervention in heart failure.