基于网络药理学及分子对接技术分析康艾注射液治疗肝细胞癌的物质基础与分子机制

目的:阐述康艾注射液(Kang’ai injection,KAI)治疗肝细胞癌(hepatocellular carcinoma,HCC)的物质基础与分子机制。方法:基于中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP),根据口服生物利用度(oral bioavailability,OB)≥30%、药物相似性(drug-likeness,DL)≥0.18筛选有效活性成分。GeneCard、OMIN、DrugBank及TTD数据库检索HCC相关靶基因。使用Cytoscape软件构建KAI-关键靶基因-HCC复合目标网络。利用String数据库构建蛋白质-蛋白质相互作用网络(protein-protein interaction,PPI)。对关键靶基因进行基于基因本体论(Gene Ontology,GO)生物功能分析及基因和基因组的京都百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。采用基因表达谱交互分析(gene expression profile interaction analysis,GEPIA)数据库对核心靶基因进行生存曲线分析。最后,对核心靶基因进行有效分子对接验证。结果:共获得52个有效活性成分调控166个关键靶基因。槲皮素、山柰酚及木犀草素是复合目标网络中主要有效活性成分。GO生物功能分析结果表明关键靶基因主要参与调节生物过程,如细胞代谢、凋亡和细胞增殖。KEGG通路富集分析显示的主要信号通路是P13K-Akt信号通路。拓扑分析示MYC、RELA、MAPK14、PPARA、CCND1、FOS、RXRA、MAPK1、AKT1、ESR1、CDKN1A、MR3C1、TP53、RB1、JUN、MAPK8是核心靶基因。RELA、MAPK1及JUN低表达的HCC患者总生存率更高(P<0.05),而ESR1高表达的HCC患者总生存率更低(P<0.05)。RELA、MAPK1、JUN及ESR1核心靶基因与KAI有效活性成分结合能均小于-5.0kcal/mol,KAI有效活性成分与核心靶基因具有较好亲和力。结论:KAI作用于多成分、多途径、多靶点协同干预治疗HCC的物质基础及分子机制,为药物开发和临床应用提供新策略。

Analysis of the material basis and molecular mechanism of Kang’ai injection in the treatment of hepatocellular carcinoma based on network pharmacology and molecular docking technology

Objective:The aim of this study was to elucidate the material basis and molecular mechanism of Kang-ai injection(KAI)in the treatment of hepatocellular carcinoma(HCC).Methods:Based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),the active ingredients were screened according to the oral bioavailability(OB)≥30%and drug similarity(DL)0.18.GeneCard、OMIN、DrugBank and TTD databases were used to search for HCC related target genes.The complex target network of KAI-key target gene-HCC was constructed by using Cytoscape software.Protein protein interaction network(PPI)was constructed by using string database.The key target genes were analyzed based on Gene Ontology(GO)biological function analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis of genes and genomes.Gene expression profile interaction analysis(GEPIA)database was used to analyze the survival of core target genes.Finally,the core target gene was verified by molecular docking.Results:A total of 52 active components were obtained to regulate 166 key target genes.Quercetin,kaempferol and luteolin are the main active components in the composite target network.GO biological function analysis showed that key target genes were mainly involved in the regulation of biological processes,such as cell metabolism,apoptosis and cell proliferation.KEGG pathway enrichment analysis showed that P13 K-Akt signaling pathway was the main signaling pathway.Topology analysis showed that MYC,RELA,MAPK14,PPARA,CCND1,FOS,RXRA,MAPK1,AKT1,ESR1,CDKN1 A,NR3 C1,TP53,RBI,JUN and MAPK8 were core target genes.The overall survival rate of HCC patients with low expression of RELA,MAPK1 and JUN was higher(P<0.05),while the overall survival rate of HCC patients with high expression of ESR1 was lower(P<0.05).The binding energies of RELA,MAPK1,JUN and ESR1 core target genes with the active components of KAI were all less than-5.0 kcal/mol,indicating that the core target genes had a good affinity with the active components of KAI.Conclusion:This study reveals the material basis and molecular mechanism of KAI acting on multi-component,multichannel and multi-target collaborative intervention treatment of HCC,and provides a new strategy for drug development and clinical application.