新烟碱类化合物与烟碱乙酰胆碱受体的相互作用及选择性研究
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摘要
本论文包括三个部分。第一章概述了烟碱乙酰胆碱受体的结构、亚型及亚基组成,归纳了几种新烟碱杀虫剂与受体的作用模式假说并且简述了计算机辅助药物设计和分子动力学方法。
第二章综合运用了同源模建、分子对接方法研究了典型新烟碱化合物与靶标的作用机制。运用分子对接的方法,评价了顺式硝基烯类化合物IPPA 156011两种构型与AChBP的结合情况,发现S构型的化合物与受体作用好,应为活性构型,而R构型化合物与受体无明显作用；同时发现结合位点水分子存在与否对化合物IPPA156011的作用模式无明显影响。通过序列比对、同源模建、分子对接研究,在一定程度上揭示了吡虫啉对桃蚜等靶标昆虫具有高杀虫活性,而对拟环纹豹蛛低活性的原因。桃蚜Mpβ1亚基和拟环纹豹蛛Ppβ1亚基在活性位点loopD存在R81Q残基的差异,桃蚜Mpβ1亚基Arg81残基带正电胍基的两个N-H可以与吡虫啉硝基的两个O原子形成两根N-H...O氢键,对吡虫啉的结合起关键作用；而环纹豹蛛Ppp1亚基在该位置相对应的残基为Gln81,与吡虫啉距离较远,无法形成氢键作用。模拟结果很好的解释了生物学实验数据。
第三章通过同源模建以及分子动力学方法模拟了吡虫啉与果蝇α7型和人中枢神经α4p2型nAChRs的动态作用情况。对两个体系分别进行了20 ns的分子动力学模拟研究,从动力学轨迹、结合自由能以及相互作用等方面进行分析,吡虫啉对昆虫和人nAChRs作用存在显著差异。在果蝇α7型nAChR体系中五个配体吡虫啉都能在结合位点与受体有稳定的作用,使受体能稳定保持活性状态；而在人α4β2型nAChR体系中其中一个配体IMI与受体的结合较弱,在动力学过程中偏离了结合口袋,而无法使受体维持通道打开的活性状态,揭示了吡虫啉高选择性的作用机制。进一步分析揭示了吡虫啉与果蝇α7型nAChR活性位点的作用机制：主要通过硝基的氢键作用、共轭部分与Tyr芳香侧链的π-π作用、水桥介导的氢键网络以及咪唑环C-H与芳香侧链的C.H…π弱氢键作用进行结合,同时验证了先前提出的新烟碱“氢键诱导增强的π-π堆积作用模型”
This dissertation consisted of three chapters. Chapter one was the review of the structure and function of nAChRs, the type of the subunit and subtype, and the interaction mechanism with neonicotinoids. Several general methods of computer aided drug design were also concluded.
Chapter two was the study of the interaction mechanism between the target and some typic neonicotinoids through homology modeling, molecular docking and the point mutant methods. The binding results of AChBP and IPPA156011 were evaluated with the molecular docking. The study suggested that water was not very important to the interaction mechanism of IPPA156011A binding with AChBP. The binding ability between imidacloprid and Myzus persicae or Pardosa pseudoanulata was compared by sequence alignment, homology modeling and molecular docking as well. The dimers of N1α1/Rp Mpβ1 and N1α1/Rp Mpβ1-3M which N1α1/Rp Mpβ1 contains R81Q、N137G、F190W three mutants were modeled by homology modeling. Then molecular docking were used to calculate the binding ability of imidacloprid and the models. Nlal/RβMpβ1 showed the direct interaction between R81 and imidacloprid, but in the model of N1α1/Rβmpβ1-3M, Q81 located apart from imidacloprid. The hydrogen bond between R81 and the nitro group of imidacloprid determined the selectivity of imidacloprid between target insects and other species.
Chapter three was the study of the selectivity of imidacloprid with Drosophila melanogasterα7 and hunmanα4β2 nAChRs by homology modeling and molecular dynamics. After modeled the two nAChR with imidacloprid and waters which were in the binding site by homology modeling,20ns molecular dynamics were taken by AMBER10 to compare the selectivity of imidacloprid between different species. The RMSD during 20ns of imidacloprid in two models showed that imidacloprid in Dα7 model was more stable than in hunmanα4β2 model. Waters in the binding site were very important in the binding between imidaclopird and Dα7 model through the calculation of hydrogen bond interaction. The waters could not only conform hydrogen bond with the residues around the binding site, but also with the nitro of imidacloprid pyridine cycle. The binding energy was also calculated by AUTODOCK4.1. The energy results suggested that imidacloprid could hold the active construction with lower binding energy in Dα7 model. Imidacloprid in hunmanα4β2 model could not keep the active construction suggested that the interaction between imidacloprid and Dα7 model were stronger than imidacloprid and hunmanα4β2 model. The interaction mechanism between imidacloprid and Dα7 model contains hydrogen bond,π-πinteraction, water bridge, C-H…πinteraction and so on.
第二章综合运用了同源模建、分子对接方法研究了典型新烟碱化合物与靶标的作用机制。运用分子对接的方法,评价了顺式硝基烯类化合物IPPA 156011两种构型与AChBP的结合情况,发现S构型的化合物与受体作用好,应为活性构型,而R构型化合物与受体无明显作用；同时发现结合位点水分子存在与否对化合物IPPA156011的作用模式无明显影响。通过序列比对、同源模建、分子对接研究,在一定程度上揭示了吡虫啉对桃蚜等靶标昆虫具有高杀虫活性,而对拟环纹豹蛛低活性的原因。桃蚜Mpβ1亚基和拟环纹豹蛛Ppβ1亚基在活性位点loopD存在R81Q残基的差异,桃蚜Mpβ1亚基Arg81残基带正电胍基的两个N-H可以与吡虫啉硝基的两个O原子形成两根N-H...O氢键,对吡虫啉的结合起关键作用；而环纹豹蛛Ppp1亚基在该位置相对应的残基为Gln81,与吡虫啉距离较远,无法形成氢键作用。模拟结果很好的解释了生物学实验数据。
第三章通过同源模建以及分子动力学方法模拟了吡虫啉与果蝇α7型和人中枢神经α4p2型nAChRs的动态作用情况。对两个体系分别进行了20 ns的分子动力学模拟研究,从动力学轨迹、结合自由能以及相互作用等方面进行分析,吡虫啉对昆虫和人nAChRs作用存在显著差异。在果蝇α7型nAChR体系中五个配体吡虫啉都能在结合位点与受体有稳定的作用,使受体能稳定保持活性状态；而在人α4β2型nAChR体系中其中一个配体IMI与受体的结合较弱,在动力学过程中偏离了结合口袋,而无法使受体维持通道打开的活性状态,揭示了吡虫啉高选择性的作用机制。进一步分析揭示了吡虫啉与果蝇α7型nAChR活性位点的作用机制：主要通过硝基的氢键作用、共轭部分与Tyr芳香侧链的π-π作用、水桥介导的氢键网络以及咪唑环C-H与芳香侧链的C.H…π弱氢键作用进行结合,同时验证了先前提出的新烟碱“氢键诱导增强的π-π堆积作用模型”
This dissertation consisted of three chapters. Chapter one was the review of the structure and function of nAChRs, the type of the subunit and subtype, and the interaction mechanism with neonicotinoids. Several general methods of computer aided drug design were also concluded.
Chapter two was the study of the interaction mechanism between the target and some typic neonicotinoids through homology modeling, molecular docking and the point mutant methods. The binding results of AChBP and IPPA156011 were evaluated with the molecular docking. The study suggested that water was not very important to the interaction mechanism of IPPA156011A binding with AChBP. The binding ability between imidacloprid and Myzus persicae or Pardosa pseudoanulata was compared by sequence alignment, homology modeling and molecular docking as well. The dimers of N1α1/Rp Mpβ1 and N1α1/Rp Mpβ1-3M which N1α1/Rp Mpβ1 contains R81Q、N137G、F190W three mutants were modeled by homology modeling. Then molecular docking were used to calculate the binding ability of imidacloprid and the models. Nlal/RβMpβ1 showed the direct interaction between R81 and imidacloprid, but in the model of N1α1/Rβmpβ1-3M, Q81 located apart from imidacloprid. The hydrogen bond between R81 and the nitro group of imidacloprid determined the selectivity of imidacloprid between target insects and other species.
Chapter three was the study of the selectivity of imidacloprid with Drosophila melanogasterα7 and hunmanα4β2 nAChRs by homology modeling and molecular dynamics. After modeled the two nAChR with imidacloprid and waters which were in the binding site by homology modeling,20ns molecular dynamics were taken by AMBER10 to compare the selectivity of imidacloprid between different species. The RMSD during 20ns of imidacloprid in two models showed that imidacloprid in Dα7 model was more stable than in hunmanα4β2 model. Waters in the binding site were very important in the binding between imidaclopird and Dα7 model through the calculation of hydrogen bond interaction. The waters could not only conform hydrogen bond with the residues around the binding site, but also with the nitro of imidacloprid pyridine cycle. The binding energy was also calculated by AUTODOCK4.1. The energy results suggested that imidacloprid could hold the active construction with lower binding energy in Dα7 model. Imidacloprid in hunmanα4β2 model could not keep the active construction suggested that the interaction between imidacloprid and Dα7 model were stronger than imidacloprid and hunmanα4β2 model. The interaction mechanism between imidacloprid and Dα7 model contains hydrogen bond,π-πinteraction, water bridge, C-H…πinteraction and so on.
引文
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