基于网络药理学和分子对接探讨八宝丹协同奥沙利铂治疗大肠癌的作用机制

Network Pharmacology and Molecular Docking Analyses of the Synergistic Mechanism of Babao Dan and Oxaliplatin in Colorectal Cancer

目的:通过网络药理学方法对八宝丹(BBD)协同奥沙利铂(L-OHP)治疗大肠癌(CRC)的机制进行分析,进一步探明BBD协同L-OHP治疗CRC的疗效机制。方法:从中药系统药理学数据库与分析平台(TCMSP)、化学专业数据库、PubChem等数据库以及查阅文献筛选中药BBD化学成分;通过GeneCards数据库获得L-OHP相关靶点;通过OMIM-GeneMap、TTD、DisGeNET、CTD、GeneCards等数据库搜索CRC相关靶点;对药物与疾病经交集映射后通过STRING数据库、CytoScape软件获得PPI蛋白互作网络与核心靶点;使用MetaScape数据库对核心靶点进行富集分析以获得GO生物进程和KEGG通路。结果:经搜索BBD含有495种化学成分,通过Swiss ADME数据库筛选出204种活性成分,再经Swiss Target Prediction数据库得到770个可能的作用靶点,再与L-OHP的775个靶点、CRC靶点交集得到74个可能潜在作用靶点。从74个交集靶点计算出的24个核心靶点,在GO生物进程上与激酶活性的正调节、细胞迁移的正调节、肽基丝氨酸修饰等反应相关;而KEGG通路分析结果显示与癌症的途径、癌症中的蛋白多糖、内分泌抵抗、癌症中的微小RNA、TNF信号通路、铂类耐药等通路有关。分子对接表明核心靶点与多数化合物具有结合能力。结论:BBD中的槲皮素-7-醇酸、环(L-酪氨酰-L-苯丙氨酰)、人参二醇等化合物可能通过EGFR、AKT1、mTOR等多靶点协同L-OHP在多条通路中发挥抗肿瘤作用。

Objective:To further explore the mechanism of Babao Dan(BBD)combined with oxaliplatin(L-OHP)in treating colorectal cancer(CRC)through a network pharmacology analysis.Methods:The analysis involved the following steps:screen the chemical components of BBD through literature review of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Chemistry Database,PubChem,and other databases;obtain L-OHP-related targets through GeneCards database;and search CRC-related targets through OMIM,GeneMap,TTD,DisGeNET,CTD,GeneCards,and other databases.After the intersection and mapping of drugs and disease,the protein-protein interaction(PPI)network and core targets were obtained using STRING database and CytoScape software.MetaScape database was used to analyze the core targets to obtain GO biological processes and KEGG pathways.Results:BBD contained 495 chemical components with 204 active components screened out through the Swiss ADME database and 770 targets were obtained through the Swiss Target Prediction database.After the intersection of BBD and 775 targets of L-OHP with the CRC targets,it resulted in 74 potential targets.Twenty-four core targets were determined from the 74 intersection targets,which were related to the positive regulation of kinase activity,the positive regulation of cell migration,and peptidyl-serine modification in GO biological process.The KEGG pathway analysis showed that the core targets were related to pathway in cancer,proteoglycan in cancer,endocrine resistance,and microRNA in cancer,TNF signaling pathway,platinum resistance,and other pathways.Molecular docking showed that the core targets could bind to the most examined compounds.Conclusion:Quercetin-7-olate,cyclo(L-tyrosyl-L-phenylalanyl),panaxadiol,and other compounds in BBD may play an anti-colorectal cancer effect in multiple pathways,including EGFR,AKT1,mTOR,and other targets in synergy with L-OHP.