基于网络药理学探讨健脾益气与活血化瘀药物配伍治疗原发性肝癌的协同机制

Synergic mechanism of strengthening spleen and replenishing qi medicine and promoting blood circulation for removing blood stasis medicine in the treatment of primary liver cancer based on network pharmacology and molecular docking

目的:通过网络药理学和分子对接法探讨健脾益气与活血化瘀药物配伍治疗原发性肝癌的活性成分和分子作用机制。方法:以临床常用健脾益气药人参、黄芪、党参和活血化瘀药丹参、莪术、川芎为例。检索TCMSP数据库,获得健脾益气药与活血化瘀药的活性成分及作用靶点;检索OMIM和GeneCards数据库,筛选出肝癌相关靶点,使用Cytoscape软件构建“药物-成分-靶点-疾病”相互作用网络;筛选关键靶点,进行GO富集和KEGG通路分析。通过Autodock软件对网络中度值较高的中药活性成分与关键靶点进行分子对接验证。结果:筛选得到健脾益气药与活血化瘀药共有活性成分5个,共同靶点93个。筛选出肝癌相关靶点14664个,获得健脾益气药和活血化瘀药治疗肝癌共同作用靶点86个。Go功能富集提示,健脾益气药和活血化瘀药的生物学过程和功能集中在转录相关功能、核受体功能、泛素化等。KEGG通路富集提示,健脾益气药和活血化瘀药的作用靶点涉及乙型肝炎、人类巨细胞病毒感染、癌症信号通路等通路。分子对接提示,中药主要活性成分与关键靶点具有良好的对接活性。结论:健脾益气药和活血化瘀药配伍,能协同发挥抗肝癌作用,具有多成分、多靶点、多通路的作用特点,为后续机制研究提供思路和参考。

Objective:To study the active components and molecular mechanism of the combination of invigorating spleen and invigorating qi medicine and promoting blood circulation for removing blood stasis medicine in the treatment of primary liver cancer(HCC)by network pharmacology and molecular docking method.Methods:Taking ginseng,astragalus membranaceus,codonopsis pilosula,salvia miltiorrhiza,zedoary rhizome,and ligusticum chuanxiong which were most frequently used in clinical as examples,the active components and target genes of strengthening spleen and replenishing qi medicine and promoting blood circulation for removing blood stasis medicine were screened by the traditional Chinese medicine system pharmacology database and analysis platform(TCMSP).HCC related targets were screened out by Online Mendelian Inheritance in Man(OMIM)and GeneCards databases.The“drug-ingredient-target-disease”network was construced by Cytoscape software.Key targets were screened by Gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis.Molecular docking was conducted between main active components with a high network medium value and the key targets by Autodock software.Results:There were 5 active components and 93 common targets of invigorating spleen and invigorating qi medicine and promoting blood circulation for removing blood stasis medicine.A total of 14,664 targets related to HCC were screened out,and 86 common targets of strengthening the spleen and replenishing qi medicine,and promoting blood circulation for removing blood stasis medicine involving HCC treatment were obtained.GO function enrichment indicated that the biological processes and functions of invigorating the spleen and invigorat-ing qi medicine and promoting blood circulation for removing blood stasis medicine focus on transcription-related functions,nuclear receptor functions,and ubiquitination.KEGG pathway enrichment showed that the action targets of invigorating spleen and invigorating qi medicine and promoting blood circulation for removing blood stasis medicine involved Hepatitis B,Human cytomegalovirus infection,Proteoglycans in cancer,and other pathways.Molecular docking showed that the main active components had good docking activity with the key targets.Conclusion:The compatibility of invigorating spleen and invigorating qi medicine and promoting blood circulation for removing blood stasis medicine could play a synergistic role in anti-HCC and had the characteristics of multiple components,multiple targets and multiple pathways,which would provide ideas and references for the follow-up mechanism research.