基于网络药理学和分子对接的半枝莲二萜类化合物抗肝癌作用机制

Anti-hepatocellular carcinoma mechanism of diterpenoids of Scutellaria barbata on based on network pharmacology and molecular docking

目的 基于网络药理学和分子对接技术探讨半枝莲二萜类成分抗肝癌的作用机制。方法 根据文献调研(1987年1月至2022年7月)获得的155个半枝莲二萜类化合物,通过SwissADME平台筛选后得到符合条件的93种活性成分,并通过Swiss Target Prediction网络平台预测得到其中65个化合物可能的作用靶点;通过GeneCards、OMIM、PharmGkb、TTD、DrugBank以及GEO、TCGA数据库获取与肝癌有关的靶点,利用Cytoscape软件构建可视化“活性成分-靶点-肝癌”网络作用图,并通过度值筛选主要活性成分;使用String平台进行蛋白质–蛋白质相互作用(PPI)网络功能富集分析,利用Cytoscape软件构建PPI可视化网络图,通过cytoHubba插件的评分规则筛选出核心靶点和关键靶点;采用R语言软件包对半枝莲二萜抗肝癌的作用靶点进行基因本体(GO)功能和京都基因和基因组数据库(KEGG)通路富集分析;使用AutoDock vina软件对主要活性成分与关键靶点进行对接分析。结果 筛选出半枝莲二萜中6种活性成分包括Scutebarbolide I、Scutebata O、Scutelinquanine D、Scutellone F、Scutellone H和Scutebarbatine J,预测得到10个抗肝癌核心靶点,其中蛋白STAT3、MAPK1、MAPK3、HSP90AA1、PIK3R1和PIK3CA为关键靶点。基因富集分析得到953个GO功能条目和137条通路(P<0.05);分子对接结果显示,半枝莲二萜活性成分与关键靶点间存在潜在结合位点;网络药理学分析表明半枝莲二萜成分可能通过肽基-丝氨酸磷酸化、肽基-丝氨酸修饰、磷酸酶结合、蛋白质丝氨酸/苏氨酸激酶活性等生物学过程,作用于STAT3、MAPK1、MAPK3、PIK3R1、PIK3CA等关键蛋白的表达,进一步调控癌症中蛋白多糖、化学致癌受体激活、催乳素信号通路、癌症程序性死亡受体配体1(PD-L1)表达和程序性死亡受体1(PD-1)检查点通路等信号通路,发挥治疗肝癌作用。结论 半枝莲二萜类化合物能够通过多分子、多靶点、多通路、多作用机制达到治疗肝癌作用。

Objective To explore the potential mechanism of diterpenoids from Scutellaria barbata against liver cancer based on network pharmacology and molecular docking method.Methods According to literature investigation(January 1987 to July 2022),155diterpenoids of S.barbata were obtained,and 93 qualified active components were obtained after screening by Swiss ADME,of which 65 compounds can predict their action targets on Swiss target prediction network platform;The targets related to liver cancer were obtained through GeneCards,OMIM,PharmGKB,TTD,DrugBank,GEO and TCGA databases.The network diagram of "active ingredient target disease" was constructed with the help of Cytoscape software,and the main active ingredients were screened through the degree value;Protein-protein interaction(PPI) analysis was carried out by String platform;PPI network diagram was made by Cytoscape software,and core targets and key targets were screened out through the score of cytohubba plug-in;The R package was used to analyze the GO function and KEGG pathway;Autodock Vina software was used for molecular docking between main active components and key targets.Results Six active diterpenoids of S.barbata were screened,including scutebarbolide I,scutebata O,scutelinquanine D,Scutellone F,Scutellone H and Scutebarbaratine J.Ten core targets were predicted,including STAT3,MAPK1,MAPK3,HSP90AA1,PIK3R1 and PIK3CA are the key targets.A total of 953 GO items and 137 pathways were obtained by gene enrichment analysis(P <0.05);The results of molecular docking showed that there were potential binding sites between the active diterpenoids of S.barbata and the key targets;Network pharmacological analysis shows that the diterpenoids of S.barbata played a role in the treatment of liver cancer,which may act on the expression of key proteins such as STAT3,MAPK1 and MAPK3,through biological processes such as peptide-serine phosphorylation,peptide-serine modification,phosphatase binding and protein serine/threonine kinase activity,and further regulate the signal pathways such as proteoglycans in cancer,chemical carcinogen receptor activation,prolactin signaling pathway,and PD-L1 expression and PD-1 checkpoint pathway in cancer,et al.Conclusion The diterpenoids of S.barbata can treat liver cancer through multi molecules,multi-target,multi-channel and multi action mechanism.