蟾酥中主要蟾毒配基类化合物的抗恶性肿瘤作用机制:基于网络药理学和分子对接的研究  

Anti-malignant tumoRmechanism of majoRbufadienolide compounds from Venenum bufonis:a research based on network pharmacology and molecula Rdocking

作　　者：李洲强 白媛媛 鲁世金[3] 马洁 朱其凤[3] 张雅靖 侯恩存[4] 吴发胜[4] LI Zhou-qiang;BAI Yuan-yuan;LU Shi-jin;MA Jie;ZHU Qi-feng;ZHANG Ya-jing;HOU En-cun;WU Fa-sheng(Department of Respiratory and Critical Care Medicine,Liuzhou Hospital of Traditional Chinese Medicine,Liuzhou 545001,Guangxi,China;Graduate School,Guangxi University of Chinese Medicine,Nanning 530001,Guangxi,China;CenteRfoRTranslational Medicine of Integrated Traditional Chinese and Western Medicine,,Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine,Nanning 530011,Guangxi,China;Department of Oncology,Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine,Nanning 530011,Guangxi,China)

机构地区：[1]柳州市中医医院呼吸与危重症医学科,广西柳州市545001 [2]广西中医药大学研究生院,南宁市530001 [3]广西中医药大学附属瑞康医院中西医结合转化医学中心,南宁市530011 [4]广西中医药大学附属瑞康医院肿瘤科,南宁市530011

出　　处：《广西医学》2022年第21期2504-2510,共7页Guangxi Medical Journal

基　　金：广西科技基地和人才专项项目(2021AC18006);广西医药卫生自筹经费科研课题(Z20190988)。

摘　　要：目的采用网络药理学方法和分子对接技术,探讨蟾酥中主要蟾毒配基类化合物抗恶性肿瘤作用的潜在分子机制。方法通过文献检索筛选出蟾酥主要抗恶性肿瘤活性成分,在SwissTargetPrediction数据库中获得对应成分的预测靶点。通过GeneCards数据库获得恶性肿瘤的全部靶点。将药物与疾病的主要靶点通过韦恩图取交集以获得共同靶点(即蟾酥抗恶性肿瘤的关键靶点),运用STRING数据库构建关键靶点的蛋白-蛋白互相作用(PPI)网络,根据度值获得核心靶点。利用DAVID数据库对关键靶点进行生物功能和通路富集分析。最后运用AutoDock 3.7软件对核心靶点与存在靶点的主要活性成分进行分子对接及可视化。结果筛选出活性成分8个(蟾毒灵、蟾毒它灵、华蟾毒它灵、华蟾酥毒基、远华蟾蜍精、日蟾蜍他灵、酯蟾毒配基、沙蟾毒精)及恶性肿瘤相关靶点500个,取交集后获得关键靶点41个。构建PPI网络并获得10个核心靶点(cyclin D1、AKT1、PIK3CA、MAPK1、EGFR、JAK2、MDM2、AR、MAPK8、MTOR)。富集分析结果表明:关键靶点可能主要在核质、细胞质基质、细胞核中,通过参与蛋白质自我磷酸化、酪氨酸肽基磷酸化等进程,作用于癌症信号通路、癌症中心碳代谢、PI3K/AKT信号通路、Ras信号通路等20条关键信号通路,从而发挥抗恶性肿瘤的作用。分子对接结果显示,配体中酯蟾毒配基、沙蟾毒精、远华蟾毒精与受体对接效果最好;核心靶点中MAPK1、EGFR、cyclin D1与配体对接效果较好。结论蟾酥中主要蟾毒配基类化合物有酯蟾毒配基、沙蟾毒精、远华蟾毒精等,它们作用于MAPK1、EGFR、cyclin D1等关键蛋白,主要在核质、细胞质基质、细胞核中参与蛋白质自我磷酸化、酪氨酸肽基磷酸化等进程作用于癌症通路信号、癌症中心碳代谢、PI3K/AKT信号通路、Ras信号通路等关键信号通路,从而共同发挥抗恶性肿瘤的Objective To explore the potential moleculaRmechanism of anti-malignant tumoRof majoRbufadienolide compounds from Venenum bufonis using the network pharmacological method and moleculaRdocking technique.Methods The majoRactive components of anti-malignant tumoRfrom Venenum bufonis were screened by the literature retrieval,and predictive targets corresponded to components were obtained from the SwissTargetPrediction database.All the targets of malignant tumors were acquired from the GeneCards database.The intersection between main targets of drugs and diseases was performed by Venn diagram to obtain common targets(i.e.the key targets of anti-malignant tumoRfrom Venenum bufonis).The protein-protein interaction(PPI)network of key targets was constructed by STRING database,and the core targets were obtained according to the degree value.The David database was used foRbiological function and pathway enrichment analysis of the key targets.Eventually,the AutoDock 3.7 software was used to perform moleculaRdocking and visualization on core targets and the majoRactive components possessing targets.Results A total of 8 active components,as foRbufalin,bufotalin,cinobufotalin,cinobufagin,telocinobufagin,gamabufotalin,resibufogenin,and arenobufagin,and 500 targets related to malignant tumors were screened,and 41 key targets were obtained afteRintersection.A total of 10 core targets(cyclin D1,AKT1,PIK3CA,MAPK1,EGFR,JAK2,MDM2,AR,MAPK8,and MTOR)were acquired by constructing PPI network.The results of enrichment analysis revealed that the key targets might be mainly in the nucleoplasm,cytoplasmic matrix and cell nucleus,and by participating in protein self-phosphorylation,tyrosine peptidyl phosphorylation and otheRprocesses,they acted on 20 key signaling pathways with respect to canceRsignaling pathway,canceRcenteRcarbon metabolism,PI3K/AKT signaling pathway,Ras signaling pathway and so on,so as to exert effect on anti-malignant tumors.The results of moleculaRdocking presented that resibufogenin,arenobufagin and telocinobufagin of

关 键 词：恶性肿瘤 蟾酥 蟾毒配基类化合物 作用机制 网络药理学 分子对接 

分 类 号：R735.7[医药卫生—肿瘤]