基于网络药理学和分子对接技术探讨替格瑞洛抗脓毒症心肌病的可能分子机制  

Exploring the potential molecular mechanism of ticagrelor against sepsisinduced cardiomyopathy based on network pharmacology and molecular docking techniques

作　　者：徐利君[1] 徐红燕[1] 陈赛贞[1] 叶佳丽 夏哲林 徐煜彬 XU Lijun;XU Hongyan;CHEN Saizhen;YE Jiali;XIA Zhelin;XU Yubin(Department of Pharmacy,Taizhou Central Hospital-Taizhou University Hospital,Taizhou 318000,China)

机构地区：[1]台州市中心医院-台州学院附属医院药剂科,台州318000

出　　处：《中国临床药学杂志》2024年第12期887-895,共9页Chinese Journal of Clinical Pharmacy

基　　金：国家自然科学基金项目(编号82374008);浙江省卫生创新人才项目;浙江省医药卫生科技厅项目(编号2024KY1823);浙江省台州市科技局科技计划项目(编号21ywa33);台州市中心医院(台州学院附属医院)专项科研基金(编号2019KT033)。

摘　　要：目的基于网络药理学方法和分子对接技术探究替格瑞洛抗脓毒症心肌病(SIC)的潜在分子机制。方法通过SwissTargetPrediction数据库预测替格瑞洛的潜在作用靶点,以及利用GeneCards、OMIM和TTD数据库获取SIC的疾病靶点后,采用韦恩图分析获得替格瑞洛抗SIC的共同靶点。通过STRING数据库构建蛋白质互作网络,借助Cytoscape 3.9.1软件对蛋白质互作网络进行可视化分析并筛选出10个核心靶点。采用DAVID数据库对核心靶点进行基因本体(GO)分析和京都基因与基因组百科全书(KEGG)富集分析,筛选替格瑞洛治疗SIC重要的信号通路。最后利用分子对接技术对关键靶蛋白和替格瑞洛的结合能力进行初步验证。结果通过网络药理学方法预测,筛选出替格瑞洛作用靶点67个,SIC潜在靶点1778个,替格瑞洛与SIC的共同靶点34个。替格瑞洛抗SIC的10个核心靶点为肿瘤坏死因子(TNF)、表皮生长因子受体(EGFR)、热休克蛋白90α家族A类成员1(HSP90AA1)、过氧化物酶体增殖物激活受体γ(PPARG)、基质金属蛋白酶9(MMP9)、NOD样受体蛋白结构域相关蛋白3(NLRP3)、Janus激酶2(JAK2)、丝裂原活化蛋白激酶1(MAPK1)、丝裂原活化蛋白激酶8(MAPK8)和多腺苷二磷酸核糖聚合酶1(PARP1)。通过对靶点的富集分析,发现替格瑞洛主要通过TNF、HSP90AA1、MAPK8、NLRP3等关键靶点,发挥干预SIC的作用。分子对接显示,替格瑞洛与核心靶点TNF、HSP90AA1、MMP9、NLRP3、MAPK8、PARP1有良好的结合力,其中与NLRP3结合能最低,为-7.16 kcal·mol^(-1)。结论替格瑞洛可能作用于TNF、HSP90AA1、MMP9、NLRP3、MAPK8、PARP1等靶点,调控细胞坏死性凋亡、白介素-17信号通路、NOD样受体信号通路等多条信号发挥抗SIC的作用。AIM To explore the potential molecular mechanism of ticagrelor in the treatment of sepsis-induced cardiomyopathy(SIC)based on network pharmacology and molecular docking technology.METHODS Potential targets of ticagrelor were identified using the SwissTargetPrediction database.Subsequently,common targets against SIC were determined by obtaining disease targets from GeneCards,OMIM,and TTD databases and analyzing the overlap with a Venn diagram.The protein-protein interaction(PPI)network was obtained through STRING database.Cytoscape 3.9.1 was used to visualize and analyze the PPI network and 10 core targets were selected.Gene ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were conducted on core targets using the DAVID database to screen for significant signaling pathways in the treatment of SIC with ticagrelor.Finally,molecular docking was performed to verify the binding capacity between ticagrelor and core targets.RESULTS Through network pharmacological prediction,67 targets for ticagrelor,1778 potential targets for septic cardiomyopathy,and 34 intersecting targets were selected.The 10 core targets in the PPI network included tumor necrosis factor(TNF),epidermal growth factor receptor(EGFR),heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator-activated receptor gamma(PPARG),matrix metalloprotein 9(MMP9),NOD-like receptor family pyrin domain-containing 3(NLRP3),Janus kinase 2(JAK2),mitogen-activated protein kinase 1(MAPK1),mitogenactivated protein kinase 8(MAPK8),poly(ADP-ribose)polymerase 1(PARP1).GO and KEGG analysis of the hub targets found that ticagrelor mainly regulated necroptosis,interleukin-17(IL-17)signaling pathway,NOD-like receptor signaling pathway and other signaling pathways through hub targets(e.g.,TNF,HSP90AA1,NLRP3).Molecular docking results showed that ticagrelor could target the core targets TNF,HSP90AA1,MMP9,NLRP3,MAPK8,and PARP1.The lowest binding energy with NLRP3 was 7.16 kcal·mol^(-1).CONCLUSION This study provides

关 键 词：替格瑞洛 脓毒症心肌病 网络药理学 分子对接 

分 类 号：R73[医药卫生—肿瘤]