亚氨基哒嗪类衍生物对人与昆虫GABA受体的选择性研究

Selectivity of Iminopyridazine Derivatives for GABA Receptors in Human Being and Insects

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 theα1β2γ2 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.