基于网络药理学及分子对接研究栀子抗缺血性脑卒中的分子机制

Network pharmacology and molecular docking-based research on the molecular mechanism of Gardeniae Fructus against cerebral ischemic stroke

目的基于网络药理学及分子对接方法,探讨栀子活性成分治疗缺血性脑卒中(CIS)的相关作用靶点及潜在分子机制。方法检索中药系统药理学数据库与分析平台(TCMSP)及国内外文献筛选获得活性成分及其对应靶点;检索GeneCards、OMIM等数据库获得CIS疾病相关靶点;采用STRING分析靶点蛋白的互作关系;利用Cytoscape软件构建并合并活性成分靶点及疾病靶点相互作用关系网络,通过网络拓扑分析筛选出关键基因,并对核心靶点进行GO和KEGG信号通路富集分析;最后,利用MOE软件对关键靶点与核心成分进行分子对接。结果共检索到98种活性成分,成分作用靶标97个,疾病靶标4409个,通过网络拓扑分析筛选出80个关键基因,功能分析富集通路129条。进一步分析栀子治疗CIS的12个核心成分与10个关键靶点,其主要作用于流体剪切应力和动脉粥样硬化、MAPK(丝裂原活化蛋白激酶)、NF-κB(核因子-κB)、VEGF(血管内皮生长因子)、血小板活化等信号通路。12个有效成分与VEGFA、MAPK8、IL6(白细胞介素6)分子对接,其结合能均≤-5 kJ/mol,各成分间结合能无显著性差异。结论本研究揭示了栀子治疗CIS具有“多成分-多靶点-多通路”调控特点,其效应机制与促进血管新生、抗炎、抗氧化应激等相关。

AIM To explore the mechanism of Gardeniae Fructus in the treatment of cerebral ischemic stroke(CIS)based on network pharmacology and molecular docking.METHODS According to the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),the library of chemical constituents and its corresponding targets of Gardeniae Fructus was established by referring to Chinese and foreign literature reports.The targets related to CIS were found through GeneCards,OMIM online analysis platform.The proteinprotein interaction(PPI)network was constructed and analyzed by STRING database.The networks were merged and then analysed through network topology to acquire the core targets using Cytoscape software,and then predicted the enrichment of GO and KEGG signaling pathways for core targets GO analysis and KEGG signal pathway enrichment analysis.Finally,MOE software was used for molecular docking in key targets and core components.RESULTS A total of 98 corresponding components and 97 predicted targets of Gardeniae Fructus in the TCMSP database,and 4409 disease targets were retrieved.Based on network topology analysis,80 key targets of Gardeniae Fructus in treating CIS were screened out.GO and KEGG biological process analysis revealed 129 biological processes.Further analysis on the 12 core components and 10 key targets of Gardeniae Fructus for CIS treatment,turned out that they mainly acted on the signal pathways of fluid shear stress and atherosclerosis,MAPK,NF-κB,VEGF,platelet activation and so on;and the 12 core components respectively docked with vascular endothelial growth factor(VEGFA),mitogen-activated protein kinase 8(MAPK8),and interleukin 6(IL6).The binding energy was lower than-5 kJ/mol,and no significant difference in binding energy between any two components was observed.CONCLUSION This study reveals the“multi-components,multi-targets,multipathways”features of Gardeniae Fructus in treatment of CIS.The mechanism may be associated with the promotion of angiogenesis,anti-inflammatory,and anti-oxidative stress.