基于网络药理学和分子对接探讨肉苁蓉治疗帕金森病的作用机制

徐朝辉; 邹苑; 陈瑛; 梁彪; 赵卿

doi:10.13386/j.issn1002-0306.2021100009

基于网络药理学和分子对接探讨肉苁蓉治疗帕金森病的作用机制

Mechanism of Cistanches Herba in Treatment of Parkinson’s Disease Based on Network Pharmacology and Molecular Docking

摘要

摘要: 基于网络药理学及分子对接对肉苁蓉治疗帕金森疾病的作用机制进行研究。利用 TCMSP筛选肉苁蓉中的活性成分作为候选化合物，再利用PubChem和sea数据库获取肉苁蓉的靶点信息。在GeneCard数据库中获取帕金森病靶点信息，通过比对中药和疾病靶点，得到共有靶点基因信息。运用STRING进行靶点蛋白互作（protein-protein interaction，PPI）网络的构建，在DAVID6.8数据库中对关键靶基因进行基因本体（gene ontology，GO）富集和基因组百科全书（Kyoto encyclopedia of genes and geomes，KEGG）通路富集得出治疗靶基因，利用cytoscape软件构建中药-化合物-靶点网络图。并将该网络中的基因靶点以degree值高低进行排序，选择前5个关键靶点，最后利用AutoDock Vina工具将5个关键靶点与肉苁蓉有效活性成分进行分子对接。结果表明：从肉苁蓉中共筛选得到6个有效活性成分，分别为β-谷甾醇、花生四烯酸、脱水内酯、丁香树脂二甲醚、槲皮素、枫马京。交集获得308个预测靶点，将其进行PPI分析，并从中筛选出38个关键靶基因，对关键靶基因进行GO与KEGG通路富集。最终发现，GO富集中生物过程（biologica process，BP）包括细胞内信号转导等；细胞成分（cellular component，CC）分析主要为蛋白质复合物、线粒体等；分子功能（molecular function，MF）结果主要为腺嘌呤核苷三磷酸结合、蛋白质复合物结合等。KEGG通路富集主要包括磷脂酰肌醇-3-激酶（phosphatidylin-ositol-3-kinase，PI3K）/蛋白激酶B（Protein Kinase B，PKB/AKT）、微型核醣核酸（microRNAs，miRNAs）、缺氧诱导因子-1（hypoxia inducible factor-1，HIF-1）、肿瘤坏死因子（tumor necrosis factor，TNF）、叉形头转录因子O亚型（forkhead box O，FOXO）等相关信号通路。筛选前5个关键靶点分别为MAPK8、ESR1、SRC、JAK2、AKT1。分子对接结果显示肉苁蓉6个有效活性成分与5个关键靶点具有较好的结合活性，结合能均小于−5 kcal/mol。本研究得出肉苁蓉通过保护线粒体功能、调节蛋白质活动、调节自噬、抑制神经炎症反应等治疗帕金森病，发挥多成分、多通路、多靶点协同作用。

Abstract: The study aimed to explore the mechanism of Cistanches Herba in treatment of Parkinson’s disease based on network pharmacology and molecular docking. The active components in Cistanches Herba were selected as candidate compounds by the TCMSP. And the target information of Cistanches Herba was obtained by PubChem and sea database. The target information of Parkinson’s disease was obtained by GeneCard database and the common target gene information was obtained by comparing traditional Chinese medicine and disease targets. PPI network was constructed by means of STRING. The key target genes were enriched by GO and KEGG pathway in DAVID 6.8 database. The Cytoscape software was applied to construct the network diagram of traditional Chinese medicine-chemical compound-target. The gene targets in the network were sorted according to the degree value, the first five key targets were selected. Finally, the five key targets were in connection with the effective active components of Cistanches Herba by using AutoDock Vina tool. In the end, the results showed that 6 active components were screened from Cistanches Herba beta-sitosterol, arachidonate, suchilactone, Yangambin, quercetin, Marckine. 308 prediction targets were obtained by intersection, which were analyzed by PPI. 38 key target genes were filtered out, and the key target genes were enriched by GO and KEGG pathway. Finally, it was found that GO rich BP includes intracellular signal transduction; CC analysis mainly included protein complex, mitochondrion; MF results mainly included ATP binding, protein complex binding. KEGG pathway enrichment mainly included PI3K/Akt, miRNAs, HIF-1, TNF, FOXO signal pathways, etc. The first five key targets were MAPK8, ESR1, SRC, JAK2 and AKT1. The results of molecular docking showed that the six active components of Cistanches Herba had good binding activity with five key targets. This study found that Cistanches Herba could play a multi-component, multi-channel and multi-target synergistic role in the treatment of Parkinson's disease by protecting mitochondrial function, regulating protein activity, regulating autophagy and inhibiting neuroinflammatory response.