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[1]巨修练,王黎丽,李科.斑马鱼A型γ氨基丁酸受体同源模建及分子对接[J].武汉工程大学学报,2013,(06):20-29.[doi:103969/jissn16742869201306005]
　JU Xiu lian,WANG LI li,LI Ke.Homology modeling and docking of zebrafish γaminobutyric acid receptor[J].Journal of Wuhan Institute of Technology,2013,(06):20-29.[doi:103969/jissn16742869201306005]
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斑马鱼A型γ氨基丁酸受体同源模建及分子对接(/HTML)
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《武汉工程大学学报》[ISSN:1674-2869/CN:42-1779/TQ]

卷:
期数:
2013年06期
页码:
20-29
栏目:
化学与化学工程
出版日期:
2013-06-30

文章信息/Info

Title:
Homology modeling and docking of zebrafish γaminobutyric acid receptor
文章编号:
16742869(2013)06002010
作者:
巨修练; 王黎丽; 李科
武汉工程大学化工与制药学院，绿色化工过程教育部重点实验室，湖北 武汉 430074
Author(s):
JU Xiulian; WANG LIli; LI Ke
Key Laboratory for Green Chemical Process of Ministry of Education, Wuhan Institute of Technology, Wuhan 430074, China
关键词:
氟虫腈; 毒性机理; 同源模建; 分子对接
Keywords:
fipronil;  toxic mechanism;  homology modeling;  surflexdocking
分类号:
R914.2
DOI:
103969/jissn16742869201306005
文献标志码:
A
摘要:
为了研究杀虫剂氟虫腈对斑马鱼的毒性机理，以秀丽隐杆线虫谷氨酸受体\[在蛋白质数据库（Protein Data Bank，PDB）登记号为3RHW\]作为模板，通过蛋白质同源模建的方法构建了斑马鱼A型γ氨基丁酸受体跨膜段,利用分子动力学和拉氏图验证了模型的合理性.将构建的模型与氟虫腈及其衍生物进行分子对接.氟虫腈及其衍生物与跨膜蛋白对接结果在分子水平上解释了氟虫腈对斑马鱼的毒性机理：10个不同构象的氟虫腈与跨膜蛋白对接各个打分和结合自由能都比较稳定，氟虫腈垂直地定位于跨膜段的胞质端，跨膜蛋白上28位天冬酰胺和38位精氨酸与氟虫腈分子产生氢键；苯环上的取代基CF3,Cl,Cl和吡唑环上取代基SOCF3或SO2CF3是产生毒性作用的重要基团；基于氟虫腈结构虚拟筛选的化合物与跨膜蛋白的对接结果也进一步验证了上述结论.
Abstract:
To explore the toxicity of fipronil with zebrafish, threedimensional (3D) model of transmembrane domain of zebrafish γaminobutyric acid receptor was generated by homology modeling, using Caenorhabditis elegans glutamategated ion channel receptor as a template (PDB registration number 3RHW). The conformational stability of the model was studied by molecular dynamics (MD) and the quality of the model was confirmed. Furthermore, fipronil and its derivatives were docked into the putative binding site of transmembrane domain of zebrafish γaminobutyric acid receptor model by Surflexdocking. The toxicity mechanism is explained by docking results: docking score and free energy of 10 different conformation fipronil binding with receptor are stable, fipronil is vertically fixed position to cytoplasmic side of the transmembrane domain, transmembrane receptor on 28 asparagine and 38 arginine produce hydrogen bonding with fipronil; The substituent groups CF3,Cl,Cl of benzene ring and the substituent SOCF3 or SO2CF3 of pyrazole ring are important in producing toxicity. The conclusions are proved through the result of virtual screening compounds docking with receptor.

参考文献/References:

［1］巨修练．GABAA受体及其非竞争性拮抗剂的研究进展\[J\]．世界农药，2007，29（1）：2833．JU Xiulian. Progress in Study of GABAA Receptor and Its Noncompetitive Antagonists\[J\].World Pesticides, 2007,29(1):2833.(in chinese)［2］王秀坤.NIELSEN M．GABAA受体药理学研究进展\[J\]．国外医学药学分册，2001，28（1）：2934．WANG Xiukun, NIELSEN M .Progress in Study of GABAA Receptor pharmacology\[J\].Foreign Medical Sciences section on Pharmacy, 2001,28(1):2934.(in chinese)［3］王世明，张颖奇，李晓立．GABAA受体研究进展\[J\]．中国局解手术学杂志，2001，10（3）：307308．WANG Shiming, ZHANG Yingqi, Li Xiaoli.Progress in Study of GABAA Receptor\[J\].Chin J Regional Anat & Operative Surg, 2001,10(3):307308.(in chinese)［4］O’MARA M, CROMER B, PARKER M, et al. Homology model of the GABAA receptor examined using Brownian dynamics\[J\]. Biophysical Journal, 2005, 88(5): 32863299.［5］HOSIE A M, ARONSTEIN K, SATTELLE D B, et al. Molecular biology of insect neuronal GABA receptors\[J\]. Trends in Neurosciences, 1997, 20(12): 578583.［6］PERRET P, SARDA X, WOLFF M, et al. Interaction of noncompetitive blockers within the gammaaminobutyric acid type A chloride Channel using chemically reactive probes as chemical sensors for cysteine mutants\[J\]. Journal of Biological Chemistry, 1999, 274(36): 2535025354.［7］CHEBIB M, JOHNSTON G A. GABAActivated ligand gated ion channels: medicinal chemistry and molecular biology\[J\]. Journal of Medicinal Chemistry, 2000, 43(8): 14271447.［8］FUCILE S, DE SAINT JAN D, DAVIDWATINE B, et al. Comparison of glycine and GABA actions on the zebrafish homomeric glycine receptor\[J\]. The Journal of Physiology, 1999, 517 ( Pt 2)(2): 369383.［9］GUSTAV A, LI Ping, BRACAMONTES J, et al. Pharmacology of structural changes at the GABAA receptor transmitter binging site\[J\]. Birtish Journal of Pharmacology, 2011, 162: 840850.［10］张瑞华，李丽琴，王惠芳，等．A型γ氨基丁酸受体结构及其有关药物\[J\]．生命的化学，2003，23(6):441443．ZHANG Ruihua, LI Liqin, WANG Huifang, et al. Structure and Related Drugs to GABAA Receptors\[J\]. Chemistry of life, 2003,23(6):441443.(in chinese)［11］ZHANG Rongwei, WEI Hongping, XIA Yimeng, et al. Development of light response and GABAergic excitationtoinhibition Switch in zebrafish retinal ganglion cells\[J\]. The Journal of Physiology, 2010, 588(Pt 14): 25572569.［12］GOLDSCHENOHM M P, WAGNER D A, PETROU S, et al. An epilepsyrelated region in the GABA(A) receptor mediates longdistance effects on GABA and benzodiazepine binding sites\[J\]. Molecular Pharmacology, 2010, 77(1): 3545.［13］CHEN Ligong, DURKIN K A, CASIDA J E. Spontaneous mobility of GABAA receptor M2 extracellular half relative to noncompetitive antagonist action\[J\]. The Journal of Biological Chemistry, 2006, 281(50): 3887138878.［14］TASNEEM A, IYER L M, JAKOBSSON E, et al. Identification of the prokaryotic ligandgated ion channels and their implications for the mechanisms and origins of animal Cysloop ion channels\[J\]. Genome Biology, 2005, 6(1): R4.［15］HINZ F I, DIETERICH D C, TIRRELL D A, et al. Noncanonical amino acid labeling in vivo to visualize and affinity purify newly synthesized proteins in larval zebrafish\[J\]. ACS Chemical Neuroscience, 2012, 3(1): 4049.［16］OGGIER D M, WEISBROD C J, STOLLER A M, et al. Effects of diazepam on gene expression and Link to physiological effects in different Life stages in zebrafish Danio rerio\[J\]. Environmental Science & Technology, 2010, 44(19): 76857691.［17］ZHOU Pei, LU Yitong, LIU Baofeng, et al. Dynamics of fipronil residue in vegetablefield ecosystem\[J\]. Chemosphere, 2004, 57(11): 16911696.［18］ZHAO X L, YEH J Z, SALGADO V L, et al. Fipronil is a potent open Channel blocker of glutamateactivated chloride channels in cockroach neurons\[J\]. The Journal of Pharmacology and Experimental Therapeutics, 2004, 310(1): 192201.［19］CORRINGER P J, BAADEN M, BOCQUET N, et al. Atomic structure and dynamics of pentameric ligandgated ion channels: new insight from bacterial homologues\[J\]. The Journal of Physiology, 2010, 588(Pt 4): 565572.［20］CHEN Ligong, DURKIN K A, CASIDA J E. Structural model for gammaaminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site\[J\]. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(13): 51855190.［21］MITEVA M A, LEE W H, MONTES M O, et al. Fast structurebased virtual ligand screening combining FRED, DOCK, and Surflex\[J\]. Journal of Medicinal Chemistry, 2005, 48(19): 60126022.［22］CHENG Jin, JU Xiulian, CHEN Xiangyang, et al. Homology modeling of human α1β2γ2 and house fly β3 GABA receptor channels and Surflexdocking of fipronil\[J\]. Journal of Molecular Modeling, 2009, 15: 11451153.

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备注/Memo

备注/Memo:
收稿日期：20130125作者简介：巨修练（1959），男，陕西乾县人，教授，博士，博士研究生导师.研究方向：计算机药物辅助设计、新农药研发、生物活性测试.
更新日期/Last Update: 2013-07-11