摘要
目的 基于网络药理学和分子对接技术探讨补肺活血(Bufeihuoxue,BFHX)胶囊治疗矽肺的作用机制.方法 通过中药系统药理学(TCMSP)数据库与分析平台、SymMap、Swiss Target Prediction数据库及文献研究获取BFHX活性成分及靶点,利用GeneCards、DisGeNET和CTD数据库筛选矽肺作用靶点,并与BFHX靶点进行交集获取重叠靶点,通过String数据库、Cytoscape 3.10.0软件构建重叠靶点蛋白互作网络及"药物—活性成分—靶点—疾病"网络,筛选BFHX胶囊治疗矽肺的Hub靶点和关键活性成分;利用David平台对重叠靶点进行基因本体论(GO)生物学功能分析及京都基因和基因组百科全书(KEGG)信号通路富集分析,进一步构建活性成分—靶点—通路网络,最后运用Meastro软件对关键活性成分与对应Hub靶点进行分子对接验证.结果 分析共获得62个BFHX活性成分、1 537个矽肺靶点、745个药物作用靶点,交集后得到127个重叠靶点;网络拓扑分析筛选出槲皮素、山奈酚、异鼠李素、黄芩素4个关键活性成分,Myc原癌基因蛋白(MYC)、表皮生长因子受体(EGFR)、核因子Kappa B亚基1(NF-κB1)、转录因子Jun(JUN)、基质金属蛋白酶9(MMP9)、前列腺素内过氧化物合酶2(PTGS2)、白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)、热休克蛋白 HSP 90β(HSP90AB1)、NF-Kappa-B 抑制剂α(NF-κBIA)、蛋白 c-Fos(FOS)、过氧化物酶体增殖物激活受体γ(PPARG)等12个Hub靶点;KEGG通路涉及白细胞介素-17(IL-17)/松弛素/C型凝集素受体/Th17细胞分化/肿瘤坏死因子(TNF)信号通路;分子对接显示,关键活性成分与对应Hub靶点均具有较好结合稳定性,其中槲皮素与EGFR对接活性最好,提示槲皮素可能是治疗矽肺的重要活性成分.结论 BFHX胶囊治疗矽肺的活性成分有槲皮素、山奈酚、异鼠李素、黄芩素;可能通过作用于EGFR、MMP9、PTGS2等靶点参与IL-17等信号通路,发挥抗感染、抗菌机制,达到缓解矽肺纤维化的作用.
Abstract
Objective To explore the mechanism of Bufeihuoxue(BFHX)capsule in the treatment of silicosis based on net-work pharmacology and molecular docking technology.Methods The active ingredients and targets of BFHX were firstly ob-tained through the Traditional Chinese Medicine System Pharmacology(TCMSP)database and analysis platform,SymMap,Swiss Target Prediction database and literature research,then using GeneCards,DisGeNET and CTD databases to screen silicosis action targets and intersecting with BFHX targets to obtain overlapping targets,subsequently,the String database and Cytoscape 3.10.0 software werc used to construct overlapping the target-protein interaction networks and the drug—active ingredient—tar-get—disease networks,thereby to screen the Hub targets and key active ingredients for BFHX capsule treatment of silicosis.Additionally,utilizing the David database platform to perform the analysis of gene ontology(GO)biological function and the analysis of Kyoto encyclopedia of gene and genomes(KEGG)signal pathway enrichment on overlapping targets,and further con-structing the active ingredient—target—pathway network,finally,using Meastro software to perform molecular docking verifica-tion between the key active ingredients and the corresponding Hub targets.Results The results showed that through analysis,a total of 62 active ingredients of BFHX,1 537 silicosis targets,745 drug action targets were obtained,and there were 127 overlap-ping targets gotten through intersection analysis;the network topology analysis identified four key active ingredients:quercetin,kaempferol,isorhamnetin and baicalein,as well as 12 hub targets,including Myc proto-oncogene protein(MYC),epidenmal growth factor receptor(EGFR),nuclear factor Kappa B subunit 1(NF-κB1),transcription factor jun(JUN),matrix metallo-proteinase 9(MMP9),prostaglandin endoperoxide synthase 2(PTGS2),interleukin-6(IL-6),interleukin-1 β(IL-1β),heat shock protein HSP 90β(HSP90AB1),NF-Kappa-B inhibitor α(NF-κBIA),protein c-Fos(FOS),peroxisome proliferator-activated receptor γ(PPARG);the KEGG pathway involved interleukin-17(IL-17)/relaxin/C-type lectin receptor/Th17 cell differentiation/tumor necrosis factor(TNF)signaling pathway;the molecular docking showed that the key active ingredients had good binding stability with the corresponding Hub targets,among which quercetin and EGFR had the best docking activity,sug-gesting that quercetin may be an important active ingredient for the treatment of silicosis:Conclusion The results suggested that the active ingredients of BFHX capsule for treating silicosis included quercetin,kaempferol,isorhamnetin and baicalein,which may participate in the signaling pathways of IL-17 by acting on such targets as EGFR,MMP9,PTGS2,and alleviate sili-cosis fibrosis by exerting the anti-inflammatory and anti-bacteria mechanisms.
维普
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