| 3,790 | 33 | 124 |
| 下载次数 | 被引频次 | 阅读次数 |
目的:基于网络药理学和分子对接技术,探寻黄连解毒汤治疗新型冠状病毒肺炎(COVID-19)的物质基础和作用机制。方法:利用TCMSP和Stitch及文献资料的检索,得到黄连解毒汤的化学成分和作用靶点。通过Cytoscape 3.3.0构建化合物-靶点网络图,Cludterirofiler对药物与疾病相同靶蛋白进行GO功能富集分析和KEGG通路富集分析。使用Autodock Vina软件进行分子对接,根据结合能和药物主要成分选择最佳的结合靶点。结果:研究共筛选出66个化合物和相应靶点239个,关键化合物主要有槲皮素、豆甾醇、山柰酚、汉黄芩素、谷甾醇、黄芩素、甲基黄连碱等,靶点涉及PTGS1、PTGS2、HSP90AA1、PRKACA、SCN5A等。GO功能富集分析生物过程主要集中于氧化应激、脂多糖、细菌的反应和凋亡信号通路的调节等。KEGG通路富集筛选信号通路(P<0.05),涉及糖尿病并发症中的AGE-RAGE信号通路、疱疹病毒感染、IL-17信号通路、TNF信号通路和甲型流感等。分子对接结果显示小檗碱、槲皮素、黄连碱、黄芩素主要化合物与SARS-CoV-2 3CL水解酶的结合能均高于参照药物的亲和力。结论:黄连解毒汤中的活性化合物能通过与新型冠状病毒3CL水解酶结合作用于PTGS2、HSP90AA1、ESR1等靶点调节,从而有可能对COVID-19有治疗作用。
Abstract：Objective: To explore the material basis and mechanism of Huanglian Jiedu Decoction in the treatment of coronavirus disease 2019(COVID-19), by using network pharmacology and molecular docking technology. Methods: The chemical composition and action targets of Huanglian Jiedu Decoction studied by TCMSP, Stitch database and literature mining methods. Cytoscape 3.3.0 was used to construct the compound-target network map, The GO function enrichment and KEGG pathway analysis of the target protein was carried out by Cludterirofiler. Autodock Vina software was used for molecular docking, then the best binding target was selected according to the binding energy and the main components. Results: 66 compounds and 239 corresponding targets were screened, the key compounds were quercetin, stigmasterol, kaempferol, wogonin, beta-sitosterol, baicalein and worenine, etc, and the key targets involved PTGS1, PTGS2, HSP90 AA1, PRKACA and SCN5 A, etc. The function enrichment analysis of GO mainly focused on lipopolysaccharide, response to molecule of bacterial origin, response to oxidative stress and regulation of apoptotic signaling pathway. In KEGG pathway enrichment screening, AGE-RAGE signaling pathway in diabetic complications, Kaposi sarcoma?associated herpesvirus infection, IL-17 signaling pathway, TNF signaling pathway and Influenza A pathway were involved. Molecular docking results demonstrated that the binding energies of core compounds(berberine, quercetin, coptisine, baicalein) and COVID-19 coronavirus 3 CL hydrolase were higher than the affinity of the reference drug. Conclusion: The active compounds of Huanglian Jiedu Decoction can bind novel coronavirus 3 CL hydrolase on targets such as PTGS2, HSP90 AA1, and ESR1, which may have a therapeutic effect on COVID-19.
[1]Weier Wang,Jianming Tang,Fangqiang Wei.Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan,China[J].J Med Virol,2020,92(4):441-447.
[2]中华预防医学会新型冠状病毒肺炎防控专家组.新型冠状病毒肺炎流行病学特征的最新认识[J].中华流行病学杂志,2020,(2):139～144.
[3]世卫组织总干事在关于 2019 新型冠状病毒的《国际卫生条例》突发事件委员会新闻通报会上的发言[OB/OL].https://www.who.int/zh/dg/speeches/detail/who-director-general-s-statement-onihr-emergency-committee-on-novel-coronavirus-(2019-ncov).
[4]新华网.世卫组织将新冠肺炎命名为"COVID-19"[EB/OL].[2020-02-12].http://m.xinhuanet.com/world/2020-02/12/c_1210470951.htm.
[5]国家卫生健康委员会.新型冠状病毒肺炎诊疗方案(试行第六版)[OB/OL].[2020-02-19].http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2.shtml.
[6]国家卫生健康委员会.新型冠状病毒肺炎诊疗方案(试行第三版)[OB/OL].[2020-01-23].http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2.shtml.
[7]张稚鲲,王若尧,陈仁寿.古今肺系疫病方配伍特点对比研究[J].中医药信息,2018,35(4):73-76.
[8]刘菊,崔瑛,白明学,等.基于中医药预防治疗新型冠状病毒肺炎的用药探析[J].中草药,1-5 [2020-03-05].http://kns.cnki.net/kcms/detail/12.1108.R.20200212.1133.002.html.
[9]田景振,杨振宁.中医药抗病毒研究思路、理论创新与基本路径[J].山东中医杂志,2018,37(6):439～444.
[10]赵娜,贾连群,徐丽,等.黄连解毒汤的文献分析研究[J].辽宁中医杂志,2018,45(8):1577～1580.
[11]权伟,张利军,陈宁,等.黄连素通过PI3K抑制肺炎衣原体感染诱导的血管内皮细胞迁移[J].中国动脉硬化杂志,2009,17(11):877-881.
[12]赖韶钦,李晓君,谭俊青,等.黄连等4种中药颗粒剂对碳青霉烯类耐药肺炎克雷伯菌细胞通透性影响[J].中医药临床杂志,2019,31(7):1317～1319.
[13]王斐,刘洁.黄连解毒汤灌肠联合全身擦浴治疗重度颅脑损伤合并肺部感染患者的效果观察[J].实用临床医药杂志,2019,23(5):60～62.
[14]赵东凯,王檀.应用黄连解毒汤合苇茎汤治疗肺炎(热毒聚肺型)38例临床观察[J].中国医药指南,2011,9(25):124～125.
[15]张庆莲,黄娟,邵单炫,等.黄连抗菌作用研究进展[J].中医药信息,2019,36(5):125～127.
[16]Sun J H,Sun F,Yan B,et al.Data mining and systematic pharmacology to reveal the mechanisms of traditional Chinese medicine in Mycoplasma pneumoniae pneumonia treatment[J].Biomed Pharmacother,2020,125:109900.
[17]龙宇,向燕,谭裕君,等.黄芩苷药理作用及新剂型的研究进展[J].中草药,2019,50(24):6142～6148.
[18]袁源见,王小青,陈超,等.栀子苷的药理作用研究新进展[J].中兽医医药杂志,2019,38(6):20～23.
[19]Boezio B,Audouze K,Ducrot P,et al.Network-based Approaches in Pharmacology[J].Mol Inform,2017,36(10):1700048.
[20]Morris G M,Limwilby M.Molecular docking[J].Methods Mol Biol,2008,443:365-382.
[21]Ru J,Li P,Wang J,et al.TCMSP:a database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminform,2014,(6):13.
[22]Soudy M,Anwar A M,Ahmed E A,et al.UniprotR:Retrieving and visualizing protein sequence and functional information from Universal Protein Resource (UniProt knowledgebase Proteomics,2020,213:103613.
[23]Smoot M E,Ono K,Ruscheinski J,et al.Cytoscape 2.8:new features for data integration and network visualization[J].Bioinformatics,2011,27(3):431～432.
[24]Huang da W,Sherman B T,Lempilcki R A.Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J].Nat Protoc,2009,4(1):44～57.
[25]Hsin K Y,Ghosh S,Kitano H.Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J].PLoS One,2013,8(12):e83922.
[26]陈丹龙,杨芳,罗志英,等.全球抗新型冠状病毒药物研发现状和瓶颈[J].中国药理学通报,2020,(4):1-11[2020-03-05].http://kns.cnki.net/kcms/detail/34.1086.r.20200220.1420.002.html.
[27]胡利琳,王玮珺,朱清静,等.新型冠状病毒肺炎相关肝损伤:病因分析及治疗策略[J].中华肝脏病杂志,2020,28(2):E001～E001.
[28]刘川,江自成,邵初晓,等.新型冠状病毒肺炎与肝功能损伤的关系初探:一项多中心研究[J].中华肝脏病杂志,2020,28(2):148～152.
[29]Wang M J,Yang C H,Jin Y,et al.Baicalin Inhibits Coxsackievirus B3 Replication by Reducing Cellular Lipid Synthesis[J].Am J Chin Med,2020,48(1):143～160.
[30]Zhang C,Sheng J,Li G,et al.Effects of Berberine and Its Derivatives on Cancer:A Systems Pharmacology Review[J].Front Pharmacol,2019,10:1461.
[31]Zeng Q X,Wang H Q,Wei W,et al.Synthesis and biological evaluation of berberine derivatives as a new class of broad-spectrum antiviral agents against Coxsackievirus B[J].Bioorg Chem,2020,95:103490.
[32]Luganini A,Mercorelli B,Messa L,et al.The isoquinoline alkaloid berberine inhibits human cytomegalovirus replication by interfering with the viral Immediate Early-2 (IE2) protein transactivating activity[J].Antiviral Res,2019,164:52～60.
[33]Lee B H,Chathuranga K,Uddin M B,et al.Coptidis Rhizoma extract inhibits replication of respiratory syncytial virus in vitro and in vivo by inducing antiviral state[J].J Microbiol,2017,55(6):488～498.
[34]Wu Y,Li J Q,Kim Y J,et al.In vivo and in vitro antiviral effects of berberine on influenza virus[J].Chin J Integr Med,2011,17(6):444～452.
[35]张卫英,张艺,余道军,等.黄柏提取物抗耐大环内酯类药物肺炎支原体的实验研究[J].中华全科医学,2018,16(10):1702～1705.
[36]姜盈盈,林岳.黄柏碱改善脓毒症大鼠急性肾损伤的作用及机制研究[J].中国中西医结合外科杂志,2019,25(6):882～887.
[37]Carvajal S,Perramon M,Casals G,et al.Cerium Oxide Nanoparticles Protect against Oxidant Injury and Interfere with Oxidative Mediated Kinase Signaling in Human-Derived Hepatocytes[J].Int J Mol Sci,2019,20(23):5959.
[38]Rao Z,Jordan P M,Wang Y,et al.Differential role of vacuolar (H(+))-ATPase in the expression and activity of cyclooxygenase-2 in human monocytes[J].Biochem Pharmacol,2020,175:113858.
[39]Song K H,Oh S J,Kim S,et al.HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors[J].Nat Commun,2020,11(1):562.
[40]Singhi A D,Wood L D,Parks E,et al.Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct[J].Gastroenterology,2020,158(3):573～582.e572.
[41]Soni K K,Meshram D,Lawal T O,et al.Fractions of Boswellia serrata suppress LTA4,LTC4,Cyclooxygenase-2 activities and mRNA in HL-60 Cells and reduce lung inflammation in BALB/c mice[J/OL].Curr Drug Discov Technol,[2020-01-26].http://www.eurekaselect.com/178626/article.
[42]高原雪,沈甜,何林,等.黄芩苷、栀子苷及其配伍对小胶质细胞增殖及激活后炎性因子影响[J].现代中医药,2019,39(3):106～109.
[43]万智双,熊丁,曹宸.miR-433-3p靶向MAPK8对肝癌细胞MHCC97H增殖、凋亡和迁移的调控作用[J].中国免疫学杂志,2020,36(01):57～62.
[44]王青,苏聪平,张惠敏,等.从炎性反应角度探讨清热解毒药的作用机制[J].中国中药杂志,2018,43(18):3787～3794.
[45]陈柯宇,贲涵芝,毛泽斌,等.罗米地辛与阿糖胞苷联合用药在肺腺癌细胞中介导组蛋白H3K14乙酰化提高CASP3转录活性[J/OL].中国生物化学与分子生物学报,1-14[2020-03-05].https://doi.org/10.13865/j.cnki.cjbmb.2020.02.1458.
[46]Eskandari E,DAahmareh T,Dahmardeh F,et al.Lack of relationship between PTEN 32-bp and TP53 16-bp Ins/Del polymorphisms and chronic hepatitis B virus infection[J].Virusdisease,2017,28(3):289～294.
[47]Li J,Liu Q,Huang X,et al.Transcriptional Profiling Reveals the Regulatory Role of CXCL8 in Promoting Colorectal Cancer[J].Front Genet,2019,10:1360.
[48]Xue H,Li M X.MicroRNA-150 protects against cigarette smoke-induced lung inflammation and airway epithelial cell apoptosis through repressing p53:MicroRNA-150 in CS-induced lung inflammation[J].Hum Exp Toxicol,2018,37(9):920～928.
[49]Huipao N,Borwornpnpinyo S,Wiboon Ut S,et al.P2Y6 receptors are involved in mediating the effect of inactivated avian influenza virus H5N1 on IL-6 & CXCL8 mRNA expression in respiratory epithelium[J].PLoS One,2017,12(5):e0176974.
[50]刘昌孝,伊秀林,王玉丽,等.认识新冠病毒(SARS-CoV-2)探讨抗病毒药物研发策略[J/OL].药物评价研究,1-11[2020-03-05].http://kns.cnki.net/kcms/detail/12.1409.r.20200225.0853.002.html.
[51]黄萍,高静雯,邹佳丽,等.大黄黄连泻心汤不同配伍下黄芩苷和汉黄芩苷在大鼠体内的药动学比较研究[J].世界科学技术(中医药现代化),2012,14(2):1445-1450.
[52]游丽娟,伍旭明,迟宗良.黄连-黄芩药对配伍机理研究[J].中国中医药科技,2018,25(5):672～674.
[53]王斌,李敏,侯建平,等.栀子、黄芩药材与标准品对小鼠脑缺血保护作用的研究[J].中药药理与临床,2010,26(5):74～76.
[54]韦灵玉,张玉杰,魏宝红,等.黄连黄芩及配伍诱导对大鼠肝微粒体5种CYP450亚酶活性的影响[J].中国中药杂志,2013,38(9):1426～1429.
[55]唐爽,李修洋,邸莎.黄柏的临床应用及其用量探究[J].吉林中医药,2019,39(8):1008～1012.
[56]陈阳峰,钟晓红.黄柏的药理作用及其活性成分提取[J].作物研究,2015,29(5):564～568.
基本信息:
DOI：10.13412/j.cnki.zyyl.20200308.001
中图分类号:R285.5
引用信息:
[1]王琰,吴杰,向净匀,等.基于网络药理学和分子对接法探寻黄连解毒汤治疗新型冠状病毒肺炎(COVID-19)活性化合物的研究[J].中药药理与临床,2020,36(02):73-79.DOI:10.13412/j.cnki.zyyl.20200308.001.
基金信息:
国家自然科学基金(81473385);; 陕西省自然科学基金(2018JM7111);; 陕西中医药大学学科创新团队(2019-YL13)
2020-03-09
2020-03-09
2020-03-09