益气滋阴饮治疗2型糖尿病活性成分的虚拟筛选研究
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摘要
目的:对中药方剂益气滋阴饮治疗2型糖尿病的活性成分、作用靶标和途径进行虚拟筛选研究,从分子水平上阐述该方治疗2型糖尿病的药效机制,为其推广应用和合理组方提供理论依据。方法:从《中药原植物化学成分手册》中检索出益气滋阴饮方剂10味药材中已分离得到的化学成分,从DrugBank数据库中检索出治疗2型糖尿病的药物/类药分子,在PubChem Compound数据库中下载各成分的三维分子结构,在Cerius~2 4.10软件中对其进行结构优化,建立益气滋阴饮小分子化合物数据集;以"type 2diabetes mellitus"为关键词,在治疗靶蛋白数据库中搜索及筛选出2型糖尿病的靶标蛋白,然后从治疗靶蛋白数据库中查询并下载这些蛋白质的三维立体结构;将选出的化合物分子(配体)与靶标蛋白(受体)进行对接,找出活性较高(根据Degree值与Betweenness值大小排序)的小分子和相关度较高的靶标蛋白;以筛选出的小分子化合物与靶标蛋白(如N-反式-咖啡酰酪胺分子与糖原合成酶激酶-3β)的精细对接为例,讨论配体与受体间的相互作用机制。结果:检索得到化学成分及药物/类药分子分别为732、127个,筛选出2型糖尿病的靶标蛋白30个;根据Degree值与Betweenness值大小排序,筛选出了8个活性较高的小分子化合物(如N-反式-咖啡酰酪胺、金丝桃苷等)和10个相关度较高的靶标蛋白(如碳酸酐酶1、糖原合成酶激酶-3β等);N-反式-咖啡酰酪胺与糖原合成酶激酶-3β之间可形成氢键及π烷基化相互作用,从而影响受体蛋白的结构稳定性及活性而产生降低血糖作用。结论:采用虚拟筛选研究发现,益气滋阴饮治疗2型糖尿病时既存在一个小分子化合物与多个靶标相互作用,同时又有不同小分子化合物作用于同一靶标的现象,从分子水平上揭示了其通过多组分、多靶标协同作用的机制,为开发治疗糖尿病的新药时先导化合物的筛选和结构修饰提供了参考信息。
OBJECTIVE:To conduct virtual screening for active component,target and pathway of TCM Yiqi ziyin decoction in the treatment of type 2 diabetes mellitus,and to elucidate the pharmacodynamic mechanism of this decoction in the treatment of type 2 diabetes mellitus at molecular level so as to provide theoretical basis for its popularization,application and rational organization. METHODS:Chemical compounds isolated from 10 ingredients of Yiqi ziyin decoction were retrieved from Handbook of Chemical Constituents of Original TCM Plants. Drug/drug-like molecules for the treatment of type 2 diabetes mellitus were retrieved from DrugBank database. Three-dimensional molecular structures of each component were downloaded from PubChem Compound database. The structure was optimized by using Cerius~2 4.10 software,and the small molecular data set of Yiqi ziyin decoction was established. Using"type 2 diabetes mellitus"as keywords,target protein of type 2 diabetes mellitus were retrieved and screened from target protein databases,and their three-dimensional structures were downloaded from protein database. The selected compound molecules(ligands) were docked with target proteins(receptors),and small molecules with high activity(sorted according to the values of Degree and Betweenness)and target proteins with high correlation were found. The interaction mechanism between ligand and receptor was discussed by taking the fine docking of selected small molecules with target protein(N-trans-caffeoyl tyrosine molecule and glycogen synthase kinase-3β) as an example. RESULTS:There were 732 kinds of chemical components and 127 drug/drug-like molecules;30 target proteins of type 2 diabetes mellitus were screened.According to the values of Degree and Betweenness, 8 molecules with high activity(such as N-trans-caffeoyl tyrosine,hyperin and so on)and 10 target proteins with high correlation(such as carbonic anhydrase1,glycogen synthetase kinase-3β and so on)were screened out. The interaction between N-trans-caffeoyl tyrosine and glycogen synthase kinase-3β could form hydrogen bonds and π alkylation,thus affecting the structural stability and activity of the latter and reducing blood glucose.CONCLUSIONS:In this study,it found there existed not only one molecule compound interacting with multiple targets,but also different molecule compound interacting with the same target on Yiqi Ziyin decoction for the treatment of type 2 diabetes mellitus by virtual screening,it revealed the characteristics of multi-component and multi-target synergism of TCM prescriptions at the molecular level,providing reference for screening lead compounds and structural modification of new drug for diabetes mellitus.
OBJECTIVE:To conduct virtual screening for active component,target and pathway of TCM Yiqi ziyin decoction in the treatment of type 2 diabetes mellitus,and to elucidate the pharmacodynamic mechanism of this decoction in the treatment of type 2 diabetes mellitus at molecular level so as to provide theoretical basis for its popularization,application and rational organization. METHODS:Chemical compounds isolated from 10 ingredients of Yiqi ziyin decoction were retrieved from Handbook of Chemical Constituents of Original TCM Plants. Drug/drug-like molecules for the treatment of type 2 diabetes mellitus were retrieved from DrugBank database. Three-dimensional molecular structures of each component were downloaded from PubChem Compound database. The structure was optimized by using Cerius~2 4.10 software,and the small molecular data set of Yiqi ziyin decoction was established. Using"type 2 diabetes mellitus"as keywords,target protein of type 2 diabetes mellitus were retrieved and screened from target protein databases,and their three-dimensional structures were downloaded from protein database. The selected compound molecules(ligands) were docked with target proteins(receptors),and small molecules with high activity(sorted according to the values of Degree and Betweenness)and target proteins with high correlation were found. The interaction mechanism between ligand and receptor was discussed by taking the fine docking of selected small molecules with target protein(N-trans-caffeoyl tyrosine molecule and glycogen synthase kinase-3β) as an example. RESULTS:There were 732 kinds of chemical components and 127 drug/drug-like molecules;30 target proteins of type 2 diabetes mellitus were screened.According to the values of Degree and Betweenness, 8 molecules with high activity(such as N-trans-caffeoyl tyrosine,hyperin and so on)and 10 target proteins with high correlation(such as carbonic anhydrase1,glycogen synthetase kinase-3β and so on)were screened out. The interaction between N-trans-caffeoyl tyrosine and glycogen synthase kinase-3β could form hydrogen bonds and π alkylation,thus affecting the structural stability and activity of the latter and reducing blood glucose.CONCLUSIONS:In this study,it found there existed not only one molecule compound interacting with multiple targets,but also different molecule compound interacting with the same target on Yiqi Ziyin decoction for the treatment of type 2 diabetes mellitus by virtual screening,it revealed the characteristics of multi-component and multi-target synergism of TCM prescriptions at the molecular level,providing reference for screening lead compounds and structural modification of new drug for diabetes mellitus.
引文
[1]夏中尚,杜正彩,侯小涛,等.基于755首中药处方治疗糖尿病用药规律的研究[J].中草药,2018,49(3):739-744.
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[10]周家驹,谢桂荣,严新建.中药原植物化学成分手册[M].北京:化学工业出版社,2004:1165-1211.
[11]LIPINSKI CA,LOMBARDO F,DOMINY BW,et al.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J].Adv Drug Deliv Rev,1997,23(1/2/3):3-25.
[12]KOCH M,DUIGOU T,CARBONELL P,et al.Molecular structures enumeration and virtual screening in the chemical space with RetroPath 2.0[J].J Cheminformatics,2017,9(1):64-65.
[13]赵金龙,汤顺莉,陈国铭,等.基于系统药理学的葛根芩连汤治疗2型糖尿病作用机制探讨[J].中国实验方剂学杂志,2018,24(12):199-209.
[14]GU JY,ZHANG H,XU S,et al.Drug-target network and poly pharmacology studies of a traditional chinese medicine for typeⅡdiabetes mellitus[J].Comput Biol Chem,2011,35(5):293-297.
[15]郭小华,朱燕亮,程齐来.银翘散中抗流感病毒成分与神经氨酸酶的分子对接研究[J].中国药房,2018,29(17):2351-2355.
[16]肖音,肖斌,赵娜,等.分子对接技术筛选黑沙蒿中黄酮类化合物的PPAR-γ激动活性成分[J].中国药房,2018,29(1):58-62.
[17]张向颖,郭媛媛,张莉,等.氧化应激介导糖原合成酶激酶-3β促进肝细胞凋亡[J].细胞与分子免疫学杂志,2015,31(1):27-31.
[18]杨娇,杨勇.糖原合成酶激酶-3β对不同类型肿瘤作用机制[J].医药导报,2018,37(3):273-278.
[2]张琪.张琪临床经验辑要[M].北京:中国医药科技出版社,1988:195.
[3]林晓红.益气滋阴饮治疗糖尿病164例[J].四川中医,1999,17(10):31.
[4]李瑞玲,孙俊馥,徐顺,等.白英正丁醇萃取部位的化学成分研究[J].中国药房,2016,27(30):4252-4254.
[5]郑春松,徐筱杰,叶蕻芝.川芎活血化瘀和行气止痛作用的计算机模拟研究[J].中华中医药杂志,2015,30(5):1432-1436.
[6]杨华冬,陶玲,宋晓峰.基于生物网络与表达谱信息的基因功能预测与分析综述[J].计算机与应用化学,2017,34(2):152-156.
[7]袁文锋,涂铭扬,陈超,等.基于分子对接及生物网络功能模块识别的复方丹参滴丸的网络药理学研究[J].中国药学杂志,2017,52(9):743-749.
[8]黄勇,陈晨,张志毅,等.AutoDock Vina与Discovery Studio在虚拟筛选耐药蛋白抑制剂中的比较[J].生物信息学,2012,10(4):248-253.
[9]刘福和,陈少军,倪文娟.川芎中抗血栓活性成分的计算机虚拟筛选研究[J].中国药房,2017,28(16):2182-2186.
[10]周家驹,谢桂荣,严新建.中药原植物化学成分手册[M].北京:化学工业出版社,2004:1165-1211.
[11]LIPINSKI CA,LOMBARDO F,DOMINY BW,et al.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J].Adv Drug Deliv Rev,1997,23(1/2/3):3-25.
[12]KOCH M,DUIGOU T,CARBONELL P,et al.Molecular structures enumeration and virtual screening in the chemical space with RetroPath 2.0[J].J Cheminformatics,2017,9(1):64-65.
[13]赵金龙,汤顺莉,陈国铭,等.基于系统药理学的葛根芩连汤治疗2型糖尿病作用机制探讨[J].中国实验方剂学杂志,2018,24(12):199-209.
[14]GU JY,ZHANG H,XU S,et al.Drug-target network and poly pharmacology studies of a traditional chinese medicine for typeⅡdiabetes mellitus[J].Comput Biol Chem,2011,35(5):293-297.
[15]郭小华,朱燕亮,程齐来.银翘散中抗流感病毒成分与神经氨酸酶的分子对接研究[J].中国药房,2018,29(17):2351-2355.
[16]肖音,肖斌,赵娜,等.分子对接技术筛选黑沙蒿中黄酮类化合物的PPAR-γ激动活性成分[J].中国药房,2018,29(1):58-62.
[17]张向颖,郭媛媛,张莉,等.氧化应激介导糖原合成酶激酶-3β促进肝细胞凋亡[J].细胞与分子免疫学杂志,2015,31(1):27-31.
[18]杨娇,杨勇.糖原合成酶激酶-3β对不同类型肿瘤作用机制[J].医药导报,2018,37(3):273-278.