基于网络药理学方法探讨丹参抗非小细胞肺癌的作用机制  

Mechanism of Salvia miltiorrhiza against non-small cell lung cancer based on network pharmacology

作　　者：陶淦 郭秀丽 何发键 吴求吉[1,2,3] 钟亚华[1,2,3] TAO Gan;GUO Xiuli;HE Fajian;WU Qiuji;ZHONG Yahua(Department of Radiation and Medical Oncology,Zhongnan Hospital of Wuhan University,Wuhan 430071,China;Hubei Key Laboratory of Tumor Biological Behavior,Zhongnan Hospital of Wuhan University,Wuhan 430071,China;Hubei Provincial Clinical Research Center for Cancer,Zhongnan Hospital of Wuhan University,Wuhan 430071,China)

机构地区：[1]武汉大学中南医院肿瘤放化疗科,武汉430071 [2]武汉大学中南医院肿瘤生物学行为湖北省重点实验室,武汉430071 [3]武汉大学中南医院湖北省肿瘤医学临床研究中心,武汉430071

出　　处：《药学前沿》2025年第3期361-373,共13页China Pharmacist

基　　金：国家自然科学基金青年科学基金项目(8180111798);湖北省卫生健康委员会科研项目(WJ2019H064)。

摘　　要：目的利用网络药理学和生物信息学方法及分子对接和分子动力学模拟技术探讨丹参抗非小细胞肺癌的作用机制。方法通过中药系统药理学数据库与分析平台(TCMSP)筛选丹参主要活性成分,利用SwissTargetPrediction和PharmMapper数据库对活性成分进行靶标预测,利用GeneCards、DisGeNET和在线人类孟德遗传(OMIM)数据库获得肺癌相关靶点,取二者交集为丹参-肺癌靶点。在癌症基因组图谱数据库-肺腺癌&肺鳞癌(TCGA-LUAD&LUSC)以及GSE159857数据集中作差异分析获得公共的差异表达基因,与丹参-肺癌靶点取交集后鉴定出丹参抗非小细胞肺癌的核心靶点。对核心靶点进行GO和KEGG富集分析探究其参与的生物学过程和信号通路,用STRING数据库和Cytoscape 3.10.0软件构建核心靶点的互作网络。利用AutoDock Tools 1.5.6和AutoDock Vina 1.2.0软件对核心靶点进行分子对接验证,最后采用Gromacs 2022.4软件对分子对接复合物进行分子动力学模拟分析。结果本研究中筛选出26种丹参活性成分,并鉴定了61个丹参作用非小细胞肺癌的核心靶点。丹参活性成分通过细胞周期调控、细胞外基质重塑、氧化应激反应和代谢重编程等生物学过程以及p53、聚腺苷二磷酸核糖聚合酶(PARP)、单磷酸腺苷激活的蛋白激酶(AMPK)和核因子κB(NF-κB)等信号通路治疗非小细胞肺癌,通过直接靶向细胞周期蛋白依赖性激酶(CDK)4、极光激酶B(AURKB)、Polo样激酶1(PLK1)、CDK1和胸苷酸合成酶(TYMS)抑制非小细胞肺癌恶性进展。其中丹参酮IIA与CDK4的结合能最强,二者之间能够形成稳定的复合物。结论丹参通过调控多种生物学过程、多条信号通路和多个靶点协同作用,对非小细胞肺癌产生治疗效果。Objective To explore the mechanism of Salvia miltiorrhiza in treating non-small cell lung cancer(NSCLC)using network pharmacology,bioinformatics,molecular docking,and molecular dynamics simulations.Methods The main active components of Salvia miltiorrhiza were screened from the TCMSP database.Target prediction for these active components was performed using the SwissTargetPrediction and PharmMapper databases.Lung cancer-related targets were obtained from the GeneCards,DisGeNET,and OMIM databases.The intersection of Salvia miltiorrhiza targets and lung cancer targets were identified as the Salvia miltiorrhiza-lung cancer targets.Differential analysis was conducted on TCGA-LUAD&LUSC and GSE159857 datasets to obtain common differentially expressed genes.The intersection of these genes with the Salvia miltiorrhiza-lung cancer targets was used to identify the core targets of Salvia miltiorrhiza in treating NSCLC.GO and KEGG enrichment analyses were performed to investigate the involved biological processes and signaling pathways.The protein-protein interaction network of the core targets was constructed using the STRING database and Cytoscape 3.10.0 software.Molecular docking verification of the core targets was performed using AutoDock Tools 1.5.6 and AutoDock Vina 1.2.0.Molecular dynamics simulations of the molecular docking complexes were conducted using Gromacs 2022.4 software.Results In this study,26 active components of Salvia miltiorrhiza were screened and 61 core targets of Salvia miltiorrhiza against NSCLC were identified.The active components of Salvia miltiorrhiza exert therapeutic effects on NSCLC through biological processes such as cell cycle regulation,extracellular matrix remodeling,oxidative stress response,and metabolic reprogramming,as well as through signaling pathways including p53,PARP,AMPK,and NF-κB.These components inhibit the malignant progression of NSCLC by directly targeting CDK4,AURKB,PLK1,CDK1,and TYMS.Among these,Tanshinone IIA exhibited the strongest binding affinity with CDK4,forming

关 键 词：丹参 传统中药 网络药理学 分子对接 非小细胞肺癌 

分 类 号：R966[医药卫生—药理学]