基于分子对接技术探讨残黄片退黄作用机制
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摘要
目的:通过分子对接技术研究残黄片治疗黄疸的作用机制。方法:在中药系统药理学分析平台(TCMSP)中筛选残黄片的化学成分,从比较毒理基因组数据库(CTD)和Drug Bank数据库中搜集黄疸治疗相关靶点,利用Discovery Studio2016软件Lib Dock模块进行分子对接,分析成分和靶点的相互作用和网络特征。结果:分子对接发现残黄片37个成分与锁定的孕烷受体,雄烷受体,法尼醇X受体,环氧合酶-2,单胺氧化酶A,诱导型一氧化氮合酶等14个靶点作用较强,可通过调节胆红素代谢、调控胆汁酸合成与转运、抑制免疫与炎症反应、影响肝脏胶原形成等多个途径发挥治疗黄疸作用。成分-靶点作用网络分析发现,残黄片中穆坪马兜铃酰胺,氢化小檗碱,槲皮素,去甲氧基姜黄素,黄柏酮,姜黄素,黄麻甲苷,小檗浸碱,桤木酮,柚皮素共10个成分作用于7个以上靶点,可能为其退黄主要活性成分。结论:通过分子对接揭示了残黄片可能的退黄活性成分和作用机制,有助于后续质控标准的提升和退黄机制的研究。
Objective: To explore the mechanism of treatment of jaundice with Canhuang tablets by molecular docking. Method: The compounds of Canhuang tablets were screened in traditional Chinese medicine systems pharmacology database and analysis platform( TCMSP), and targets for treatment of jaundice were collected from the comparative toxicogenomics database( CTD) and DrugBank database. Molecular docking was carry out on the LibDock module of Discovery Studio 2016 software to evaluate the compound-target interaction,and network characteristics were analyzed. Result: A total of 37 compounds in Canhuang tablets had strong interaction on 14 targets,such as pregnane receptor( PXR),constitutive androstane receptor( CAR),farnesoid X receptor( FXR), et al. These targets played an important role in the treatment of jaundice by regulating bilirubin metabolism,regulating bile acid synthesis and transport,inhibiting immune and inflammatory response,and affecting the formation of collagen in the liver. The compound-target network analysis found that moupinamide,canadine, quercetin, demethoxycurcumin, obacunone, curcumin, corchoroside A, berlambine, alnustone,naringenin were the possible main active compounds of Canhuang tablets,which could interact with more than 7 targets. Conclusion: Molecular docking reveals the possible active compounds and the mechanism of treatment of jaundice with Canhuang tablets, and which is conducive to improvement of quality control standard of this preparation and study of its mechanism for jaundice.
Objective: To explore the mechanism of treatment of jaundice with Canhuang tablets by molecular docking. Method: The compounds of Canhuang tablets were screened in traditional Chinese medicine systems pharmacology database and analysis platform( TCMSP), and targets for treatment of jaundice were collected from the comparative toxicogenomics database( CTD) and DrugBank database. Molecular docking was carry out on the LibDock module of Discovery Studio 2016 software to evaluate the compound-target interaction,and network characteristics were analyzed. Result: A total of 37 compounds in Canhuang tablets had strong interaction on 14 targets,such as pregnane receptor( PXR),constitutive androstane receptor( CAR),farnesoid X receptor( FXR), et al. These targets played an important role in the treatment of jaundice by regulating bilirubin metabolism,regulating bile acid synthesis and transport,inhibiting immune and inflammatory response,and affecting the formation of collagen in the liver. The compound-target network analysis found that moupinamide,canadine, quercetin, demethoxycurcumin, obacunone, curcumin, corchoroside A, berlambine, alnustone,naringenin were the possible main active compounds of Canhuang tablets,which could interact with more than 7 targets. Conclusion: Molecular docking reveals the possible active compounds and the mechanism of treatment of jaundice with Canhuang tablets, and which is conducive to improvement of quality control standard of this preparation and study of its mechanism for jaundice.
引文
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[6]吉日木巴图,张诗龙,范娜,等.基于超微粉碎工艺的残黄片质量稳定性提升[J].中国实验方剂学杂志,2018,24(12):9-13.
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[8]陈红鸽,韩晋,袁海龙,等.微粉化增溶技术在残黄片工艺中的应用[J].中国实验方剂学杂志,2013,19(13):14-17.
[9]张诗龙,张木子荷,凌海慧,等.残黄片对α-奈异硫氰酸酯致大鼠黄疸模型的退黄作用[J].解放军药学学报,2017,33(1):65-67.
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[11]宋向岗.基于分子对接技术探讨中药川芎治疗脑缺血的物质基础及分子作用机制[D].广州:广东药学院,2015.
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[13] Tolson A H,WANG H B. Regulation of drugmetabolizing enzymes by xenobiotic receptors:PXR and CAR[J]. Adv Drug Deliver Rev,2010,62(13):1238-1249.
[14] Forman B M,Goode E,CHEN J,et al. Identification of a nuclear receptor that is activated by farnesol metabolites[J]. Cell,1995,81(5):687-693.
[15] YAN J Y,AI G,ZHANG X J,et al. Investigations of the total flavonoids extracted from flowers of Abelmoschus manihot(L.)Medic againstα-naphthylisothiocyanate induced cholestatic liver injury in rats[J]. J Ethnopharmacol,2015,172:202-213.
[16]李顺来,王新磊,杜洪光.一类来氟米特类似物二氢乳清酸脱氢酶抑制剂作用模式的理论研究[J].计算机与应用化学,2011,28(3):325-328.
[17]王广征,王蓓,刘淑云.复方甘草酸苷治疗慢性乙型肝炎肝硬化疗效和对一氧化氮的影响[J].中国医院药学杂志,2012,32(1):43-45.
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[19] Geller D A,Billiar T R,Hatakeyama K,et al. GTP cyclohydrolase I is coinduced in hepatocytes stimulated to produce nitric oxide[J]. Biochem Biophys Res Commun,2000,276(2):633-641.
[20] Bogdan C,Werner E,Stenger S,et al. 2,4-Diamino-6-hydroxypyrimidine,an inhibitor of tetrahydrobiopterin synthesis,down-regulates the expression of inos protein and messenger rna in primary murine macrophages[J].FEBS Lett,1995,363(1/2):69-74.
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[24] Ikejima K,QU W,Stachlewitz R F,et al. Kupffer cells contain a glycine gated chloride channel[J]. Am J Physiol,1997,272(6Pt1):G1581-G1586.
[25]吴黎艳,陈芝芸,严茂祥,等.三七对酒精性肝病大鼠肝组织CYP2E1表达的影响[J].中华中医药杂志,2011,26(6):1395-1398.
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[27]何怡.酪氨酸激酶抑制剂IRESSA(易瑞莎)在肝细胞性肝癌靶向治疗中作用的研究[D].重庆:第三军医大学,2006.
[28]刘蔚. Abl酪氨酸激酶抑制剂对小鼠梗阻性肾病肾间质纤维化的影响及机制研究[D].武汉:华中科技大学,2007.
[29]徐士勋,周燊,绪扩,等.鳖甲水提物和醇提物对单胺氧化酶活性影响的研究[J].中国实验方剂学杂志,2014,20(1):139-142.
[30]李广明,周凤蕊,刘俊华,等.六味五灵片治疗乙型肝炎肝纤维化42例[J].中国实验方剂学杂志,2013,19(21):276-279.
[31] RAO S N,Head M S,Kulkarni A,et al. Validation studies of the site-directed docking program Lib Dock[J]. J Chem Inf Model,2007,47(6):2159-2171.
[32]平键,陈红云,周扬,等.毛蕊异黄酮上调过氧化物酶体增殖因子活化受体γ抑制大鼠肝星状细胞活化的研究[J].中国中药杂志,2015,40(12):2383-2388.
[33] Renga B,Mencarelli A,Migliorati M,et al. SHPdependent and-independent induction of peroxisome proliferator activated receptorγby the bile acid sensor farnesoid X receptor counter regulates the proinflammatory phenotype of liver myofibroblasts[J].Inflamm Res,2011,60(6):577-587.
[34] WANG Y D,CHEN W D,WANG M,et al. Farnesoid X receptor antagonizes nuclear factorκB in hepatic inflammatory response[J]. Hepatology,2008,48(5):1632-1643.
[35] JIANG Y Y,YU L L,WANG M H. N-transferuloyltyramine inhibits LPS-induced NO and PGE2production in RAW 264. 7 macrophages:involvement of AP-1 and MAP kinase signalling pathways[J]. Chem Biol Interact,2015,235:56-62.
[36] Pietra D,Borghini A,Bianucci A M. In vitro studies of antifibrotic and cytoprotective effects elicited by protoberberine alkaloids in human dermal fibroblasts[J].Pharmacol Rep,2015,67(6):1081-1089.
[37]张洋.纳米脂质体槲皮素对肝损伤大鼠保肝作用的研究[D].长沙:中南大学,2012.
[38]杜志云,徐学涛,潘文龙,等.姜黄素类化合物及姜黄素衍生物对酪氨酸酶抑制作用的研究[J].日用化学工业,2008,38(3):172-175.
[39] Somchit M, Changtam C, Kimseng R, et al.Demethoxycurcumin from curcuma longa rhizome suppresses i NOS induction in an in vitro inflamed human intestinal mucosa model[J]. Asian Pac J Cancer Prev,2014,15(4):1807-1810.
[40] GAO Y,HOU R,LIU F,et al. Obacunone causes sustained expression of MKP-1 thus inactivating p38MAPK to suppress pro-inflammatory mediators through intracellular MIF[J]. J Cell Biochem,2018,119(1):837-849.
[41]李香丹,刘兰,李国鑫,等.姜黄素对阻塞性黄疸模型大鼠肝损伤的保护作用及其机制[J].延边大学医学学报,2014,37(1):15-17.
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