目的 基于网络药理学和分子对接探讨关黄母颗粒治疗围绝经期综合征的分子机制。方法 通过SymMap、中国天然产物化学成分库筛选关黄母颗粒中构成药物主要化学成分,而后通过TCMSP数据库以及既往文献对查询有效化学成分的对应靶点,结果的匹配规范通过Uniprot数据库进行。运用Cytoscape 3.6.0软件构建关黄母颗粒的药物-有效成分-作用靶点网络。通过DrugBank和GeneCards数据库明确围绝经期综合征主要疾病靶点,并与关黄母颗粒有效成分靶点进行匹配而获得潜在治疗靶点。基于Metascape数据库和DAVID数据库对潜在治疗靶点进行GO生物过程、KEGG信号通路分析,构建蛋白质-蛋白质相互作用(PPI)网络并应用Cytoscape软件进行拓扑分析,应用Surflex-Dock进行分子对接。结果 共获得有效化学成分86种,通过合并及删除重复值后得到有效成分作用靶点298个,关黄母颗粒治疗围绝经期综合征的潜在靶点基因228个。基因本体论(GO)功能分析得到排名前10名的差异基因主要涉及蛋白质代谢、细胞周期、细胞器功能、染色体等方面。KEGG富集分析显示,关黄母颗粒有效成分治疗围绝经期综合征排名前10的信号通路包括血脂和动脉粥样硬化通路(lipid and atherosclerosis)、化学致癌-受体激活通路(chemical carcinogenesis-receptor activation)、磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)信号通路等。分子对接结果显示,梓醇、五羟黄酮、汉黄芩素、山柰酚、芍药苷与黏着连接蛋白β1(CTNNB1)、表皮生长因子受体(EGFR)、甘油醛-3-磷酸脱氢酶(GAPDH)、肿瘤坏死因子(TNF)、肿瘤蛋白P53(TP53)具有较好的结合活性。结论 关黄母颗粒可能通过梓醇、五羟黄酮、芍药苷等成分,通过影响EGFR、TNF及CTNNB1等关键靶点的表达治疗围绝经期综合征。

Objective To investigate the molecular mechanism of Guanhuangmu Granules in treatment of perimenopausal syndrome based on network pharmacology and molecular docking. Methods The main chemical components of Guanhuangmu Granules were screened by SymMap and Chinese natural product chemical component database, and then the corresponding targets of effective chemical components were queried by TCMSP database and previous literature, and the matching of the results was carried out by Uniprot database. Cytoscape 3.6.0 software was used to construct drug-active component-target network of Guanhuangmu Granules. The main disease targets of perimenopausal syndrome were identified through databases such as DrugBank and GeneCards, and matched with the targets of the active ingredients of Guanhuangmu Granules to obtain potential therapeutic targets. GO biological processes and KEGG signaling pathways were analyzed for potential therapeutic targets based on Metascape database and DAVID database, and protein-protein interaction (PPI) networks were constructed. Molecular docking was performed by Surflex-Dock. Results A total of 86 effective chemical components were obtained, 298 active component targets were obtained by merging and deleting duplicate values, and 228 potential target genes were obtained by Guanhuangmu granules in treatment of perimenopausal syndrome. The top 10 differential genes were mainly involved in protein metabolism, cell cycle, organelle function, and chromosome by gene ontology (GO) functional analysis. KEGG enrichment analysis showed that the top 10 signaling pathways in treatment of perimenopausal syndrome by the active components of Guanhuangmu Granules include lipid and atherosclerosis pathway, chemical carcinogenesis-receptor activation, PI3K-Akt signaling pathway. Molecular docking results showed that catalpol, pentahydroxyflavone, baicalin, kaempferol, paeoniflorin had good binding activities with CTNNB1, EGFR, GAPDH, TNF and TP53. Conclusion Guanhuangmu Granules may treat perimenopausal syndrome by influencing the expression of EGFR, TNF, CTNNB1 and other key targets through paeoniflorin, pentahydroxyflavone, catalpa and other components.

R984

新疆维吾尔自治区自然科学基金资助项目(2021D01A42)