基于网络药理学和分子对接研究丁香抗流感的作用机制

Anti-influenza Mechanisms of Flos Caryophylli(Clove) Based on Network Pharmacology and Molecular Docking

目的:探讨丁香抗流感的作用机制。方法:利用中药系统药理学数据库与分析平台(TCMSP)和既往文献筛选丁香活性成分。通过数据库SwissTarget Predictiont获得丁香活性成分的相应靶点;采用GeneCards数据库获取流感相关靶点。将二者取交集,获得共同靶点,运用Cytoscape 3.7.2构建“丁香-活性成分-靶点-疾病网络”。运用String数据库构建共同靶点的蛋白质-蛋白质相互作用(PPI)。利用Metascape进行基因本体(GO)富集分析和京都基因和基因组百科全书(KEGG)富集分析。用Autodock Vina 1.1.2对丁香活性成分与流感关键蛋白和流感病毒蛋白进行分子对接,并构建其作用网络。结果:从丁香-活性成分-流感靶点-流感网络中获得rhamnazin-3-O-β-D-glucopyranoside、isoquercitrin、quercetin-3-O-β-D-glucuronide、rhamnetin-3-O-β-D-glucuronide-6″-methyl、1,2,3,6-tetra-O-galloylglucose等28个丁香活性成分和MAPKs、TNF、AKT1、TP53、EGFR、CASP3、HSP90AA1等209个丁香治疗流感的靶点。GO富集分析和KEGG富集分析结果显示,丁香治疗流感主要与激活免疫反应,调控酶活性、细胞凋亡、细胞因子等生物过程和调控PI3K-AKT、MAPK、细胞凋亡、趋化因子、甲型流感等信号通路有关。分子对接作用网络显示28个活性成分可与HA、NA、M2等多个流感病毒蛋白结合。结论:丁香可能通过多成分与多个流感病毒蛋白结合,并作用于多靶点,调控多通路,进而影响炎症反应、免疫应答、细胞凋亡和流感病毒复制,达到治疗流感的作用。

Objective:To explore the anti-influenza mechanisms of Flos Caryophylli(clove).Methods:The active ingredients of Flos Caryophylli were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and previous literature.SwissTargetPrediction was utilized to obtain the corresponding targets of the active ingredients of Flos Caryophylli.Influenza-related targets were searched out from GeneCards.The common targets were obtained by intersection.Cytoscape 3.7.2 was employed for the construction of “Flos Caryophylli-active ingredient-target-influenza” network.String was adopted to construct a protein interaction network(PPI) of the common targets.Gene ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed by Metascape.Autodock Vina1.1.2 was used for molecular docking to study the interactions of the active ingredients of Flos Caryophylli with key influenza proteins and influenza virus proteins, and then their action network was constructed.Results:A total of 28 ingredients, such as rhamnazin-3-O-β-D-glucopyranoside, isoquercitrin, quercetin-3-O-β-D-glucuronide, rhamnetin-3-O-β-D-glucuronide-6″-methyl, and 1,2,3,6-tetra-O-galloylglucose and 209 targets of Flos Caryophylli in treatment of influenza, such as MAPKs, TNF,AKT1,TP53,EGFR,CASP3,and HSP90 AA1 were obtained in the “Flos Caryophylli-active ingredient-target-influenza” network.Immune response activation, enzyme activity regulation, apoptosis regulation, cytokine regulation, and other biological processes were mainly related to anti-influenza by Flos Caryophylli from the GO functional enrichment screening, and PI3 K-AKT,MAPK,apoptosis, chemokine, influenza A and other signaling pathways were involved from the KEGG pathway analysis.The molecular docking network showed that the 28 active ingredients could dock to multiple influenza virus proteins, such as HA,NA,and M2.Conclusion:Flos Caryophylli could interact with influenza virus proteins through multiple ingredients, and act on multiple targets and regulate multiple signaling pathways, which affected inflammatory response, immune response, apoptosis and influenza virus replication, and finally achieved the effect of inhibiting influenza.