School of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei 437100, China)
目的]基于网络药理学和分子对接研究钩藤治疗动脉粥样硬化的有效成分、靶点及通路。 [方法]利用TCMSP数据库并结合筛选条件,确定钩藤的主要有效成分和有效成分相应的靶点,构建有效成分-靶点网络；利用GeneCards、DisGeNET、OMIM及TTD数据库确定动脉粥样硬化的疾病靶点,获取药物靶点与疾病靶点的交集,并对交集靶点进行PPI网络分析、GO生物功能富集分析和KEGG通路富集分析,应用Cytoscape 3.9.0软件中的“Analyze Network”工具,构建有效成分-靶点-通路网络,筛选出核心成分、核心靶点、核心通路,并对核心成分与核心靶点之间的亲和力进行分子对接验证。 [结果]筛选出33种有效成分,其中一种有效成分没有相应的靶点,筛选出1 608个疾病靶点和115个药物与疾病的交集靶点。PPI分析得到的主要靶点为AKT1、TNF、IL-6、IL-1β、TP53、JUN、CASP3、MMP9、PTGS2等。GO生物功能富集分析获得生物过程条目22个、细胞成分条目57个、分子功能条目100个。KEGG通路富集分析筛选出20条信号通路,主要为脂质和动脉粥样硬化、MAPK、癌症信号通路等。“Analyze Network”工具构建的有效成分-靶点-通路网络,筛选出钩藤治疗动脉粥样硬化的核心成分为槲皮素、山奈酚；核心靶点为PTGS2、HSP90AA1、PTGS1；核心通路为脂质和动脉粥样硬化、MAPK信号通路。分子对接表明槲皮素和山奈酚与PTGS2、HSP90AA1、PTGS1靶点有很好的亲和力,尤其是PTGS2与槲皮素和山奈酚具有强烈的结合活性。 [结论]钩藤中的核心成分槲皮素、山奈酚可能通过脂质和动脉粥样硬化、MAPK信号通路,作用于PTGS2、HSP90AA1、PTGS1靶点,在蛋白质结合、酶结合、可识别蛋白结合的生物功能中发挥抗动脉粥样硬化作用。
Aim To study the effective components, targets and pathways of Uncaria for the treatment of atherosclerosis based on network pharmacology and molecular docking. Methods Using TCMSP database and screening conditions, the main effective components and corresponding targets of Uncaria were determined, and the effective component-target network was constructed. GeneCards, DisGeNET, OMIM and TTD databases were used to identify disease targets of atherosclerosis, and the intersection of drug targets and disease targets were obtained. PPI network analysis, GO biological function enrichment analysis and KEGG pathway enrichment analysis were performed on the intersection targets.Using “Analyze Network ”tool in Cytoscape 3.9.0, an active component-target-pathway network was constructed and the core components, core targets and core pathways were screen out. The affinity between core components and core targets were verified by molecular docking. Results Thirty-three active components were screened out, one of which had no corresponding target. A total of 1 608 disease targets and 115 drug-disease intersection targets were screened. The main targets of PPI analysis were AKT1, TNF, IL-6, IL-1β, TP53, JUN, CASP3, MMP9 and PTGS2, etc. GO biological function enrichment analysis obtained 22 items of biological processes, 57 items of cell components and 100 items of molecular function. KEGG pathway enrichment analysis screened 20 signaling pathways, mainly including lipid and atherosclerosis, MAPK, cancer signaling pathways, etc. In the effective component-target-pathway network constructed by “Analyze Network” tool, the core components of Uncaria in the treatment of atherosclerosis were selected as quercetin and kaempferol. The core targets were PTGS2, HSP90AA1 and PTGS1. The core pathways were lipid and atherosclerosis, MAPK signaling pathway. Molecular docking showed that quercetin and kaempferol had good affinity with PTGS2, HSP90AA1 and PTGS1 targets, especially PTGS2 had strong binding activity with quercetin and kaempferol. Conclusion Quercetin and kaherol, the core components of Uncaria, may act on PTGS2, HSP90AA1 and PTGS1 targets through lipid and atherosclerotic and MAPK signaling pathways, and play an anti-atherosclerotic role in the biological functions of protein binding, enzyme binding and recognized protein binding.