亚氨基哒嗪类衍生物对人与昆虫GABA受体的选择性研究
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摘要
通过同源模建的方法构建了三种昆虫(家蝇、褐飞虱和斜纹夜蛾)的离子型GABA受体模型和人的α1β2γ2 GABA受体模型,并经能量优化、动力学模拟和拉氏图分析验证了所建模型的稳定性与合理性。将GABA受体竞争性拮抗剂亚氨基哒嗪类衍生物分别与所构建模型进行分子对接研究其作用机理,结果表明,亚氨基哒嗪类衍生物在昆虫模型中的对接打分与生物活性测试结果基本吻合,其与三种昆虫GABA受体的结合模式较人的GABA受体具有差异性和选择性。从分子层面预测和解释了昆虫GABA受体竞争性拮抗剂的选择性作用机理,为研发高效、安全的新靶点杀虫剂提供了理论依据和新思路。
The ionotropic GABA receptor(GABAR)models of three kinds of insects(Musca domestica,Laodelphax striatellus and Spodopteralitura)and the α1β2γ2 GABAR model for human being were constructedby homology modeling. The stability and rationality of these models were verified by energy optimization,dynamic simulation, and Ramachandran graph analysis. The docking mechanisms of iminopyridazinederivatives as competitive antagonists of GABARs into the constructed models were investigated. The resultsindicated that the docking scores of the iminopyridazines in GABAR models of the insects were generallyconsistent with their bioactivities,while the binding patterns of iminopyridazines in GABARs of human beingand insect were different. This study predicted and explained the selectivity of competitive antagonists of insectGABARs at the molecular level and the docking mechanism,providing the theoretical basis and new ideas forthe development of new target insecticides with high efficiency and safety.
The ionotropic GABA receptor(GABAR)models of three kinds of insects(Musca domestica,Laodelphax striatellus and Spodopteralitura)and the α1β2γ2 GABAR model for human being were constructedby homology modeling. The stability and rationality of these models were verified by energy optimization,dynamic simulation, and Ramachandran graph analysis. The docking mechanisms of iminopyridazinederivatives as competitive antagonists of GABARs into the constructed models were investigated. The resultsindicated that the docking scores of the iminopyridazines in GABAR models of the insects were generallyconsistent with their bioactivities,while the binding patterns of iminopyridazines in GABARs of human beingand insect were different. This study predicted and explained the selectivity of competitive antagonists of insectGABARs at the molecular level and the docking mechanism,providing the theoretical basis and new ideas forthe development of new target insecticides with high efficiency and safety.
引文
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[19]KRALL J,JENSEN C H,S?RENSEN T E,et al.Exploring the orthosteric binding site of theγ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3-or 5-imidazolyl substituted:design,synthesis,and pharmacological evaluation[J].Journal of Medicinal Chemistry,2013,56(16):16536-16540.
[20]LIU G,FR?LUND B,OZOE F,et al.Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insectγ-aminobutyric acid receptors leading to functional selectivity[J].Insect Biochemistry and Molecular Biology,2015,66:64-71.
[2]HEANEY C F,KINNEY J W.Role of GABAB receptors in learning and memory and neurological disorders[J].Neuroscience&Biobehavioral Reviews,2016,63:1-28.
[3]CASIDA J E,DURKIN K A.Novel GABA receptor pesticide targets[J].Pesticide Biochemistry&Physiology,2015,121:22-30.
[4]BUCKINGHAM SD,IHARA M,SATTELLE DB,et al.Mechanisms of action,resistance and toxicity ofinsecticides targeting GABA receptors[J].Current Medicinal Chemistry,2017,24(27):2935-2945.
[5]MILLER P S,SMART T G.Binding,activation and modulation of Cys-loop receptors[J].Trends in Pharmacological Sciences,2010,31(4):161-174.
[6]MILLER P S,ARICESCU A R.Crystal structure of a human GABAA receptor[J].Nature,2014,512(7514):270-275.
[7]BLOOMQUIST J R.Chloride channels as tools for developing selective insecticides[J].Archives of Insect Biochemistry&Physiology,2003,54(4):145-156.
[8]FFRENCH-CONSTANT R H,WILLIAMSON M S,DAVIESTGE,et al.Ion channels as insecticide targets[J].Journal of Neurogenetics,2016,30:163-177.
[9]THOMPSON M,STEICHEN J C,FFRENCH-CONSTANTR H.Conservation of cyclodiene insecticide resistanceassociated mutations in insects[J].Insect Molecular Biology,2010,2(3):149-154.
[10]NAKAO T.Mechanisms of resistance to insecticides targeting RDL GABA receptors in planthoppers[J].Neurotoxicology,2016,60(2):293-298.[]郑小娇,李华光,刘根炎,等昆虫氨基丁酸受体竞争性拮抗剂的研究进展[J].农药学学报,2017,19(6):665-671.
[12]WERMUTH C G,BOURGUIGNON J J,SCHLEWERG,et al.Synthesis and structure-activity relationships of a series of aminopyridazine derivatives ofγ-aminobutyric acid acting as selective GABAAantagonists[J].Journal of Medicinal Chemistry,1987,30(2):239-249.
[13]JOHNSTON G A.Advantages of an antagonist:bicuculline and other GABA antagonists[J].British Journal of Pharmacology,2013,169(2):328-336.
[14]LIU G,OZOE F,FURUTA K,et al.4,5-Substituted3-isoxazolols with insecticidal activity act as competitive antagonists of housefly GABA receptors[J].Journal of Agricultural and Food Chemistry,2015,63(28):6304-6312.
[15]LIU G,FURUTA K,NAKAJIMA H,et al.Competitive antagonism of insect GABA receptors by 4-substituted5-(4-piperidyl)-3-isothiazolols[J].Bioorganic&Medicinal Chemistry,2014,22(17):4637-4645.
[16]RAHMAN M M,AKIYOSHI Y,FURUTANI S,et al.Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA[J].Bioorganic&Medicinal Chemistry,2012,20(19):5957-5964.
[17]RAHMAN M M,LIU G,FURUTA K,et al.Synthesis of 1,3-di-and 1,3,4-trisubstituted 1,6-dihydro-6-iminopyridazines as competitive antagonists of insect GABA receptors[J].Journal of Pesticide Science,2014,39(3):133-143.
[18]SANDER T,FR?LUND B,BRUUN A T,et al.New insights into the GABAA receptor structure and orthosteric ligand binding:receptor modeling guided by experimental data[J].Proteins Structure Function&Bioinformatics,2011,79(5):11458-11477.
[19]KRALL J,JENSEN C H,S?RENSEN T E,et al.Exploring the orthosteric binding site of theγ-aminobutyric acid type A receptor using 4-(piperidin-4-yl)-1-hydroxypyrazoles 3-or 5-imidazolyl substituted:design,synthesis,and pharmacological evaluation[J].Journal of Medicinal Chemistry,2013,56(16):16536-16540.
[20]LIU G,FR?LUND B,OZOE F,et al.Differential interactions of 5-(4-piperidyl)-3-isoxazolol analogues with insectγ-aminobutyric acid receptors leading to functional selectivity[J].Insect Biochemistry and Molecular Biology,2015,66:64-71.