Xu Xiaoying, Yang Zhaokai, Zhu Kai, Li Huilin, Qin Zhaohai, Duan Hongxia
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China.
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China.
J Mol Graph Model. 2020 Jul;98:107586. doi: 10.1016/j.jmgm.2020.107586. Epub 2020 Mar 14.
The nicotinic acetylcholine receptor (nAChR), as an attractive target acted by neonicotinoid insecticides, was paid more and more attention in recent years. The mode of action study on neonicotinoids toward nAChR would present significant guidance on rational molecular design to further discover new insecticides. Four neonicotinoids including commercial agents imidacloprid and flupyradifurone, two previously synthesized compounds guadipyr and ethoxythiagua in our lab were docked into a putative model of aphid and honeybee nAChR, respectively, to explore the binding and selective mechanism of neonicotinoids in this study. The obtained results showed that a traditional H-bond interaction, as a dominating electrostatic driving force, always conferred the binding of four neonicotinoids not only to target aphid receptor but also to non-target honeybee one. Four neonicotinoids almost showed uniformly binding conformation into aphid receptor, namely, a vital electronegative nitro or butenolide group to be conserved to nestle in a non-selective β subunit. The bioassay study on Aphis gossypii also confirmed to be their excellent insecticidal activity with a lower LC value of 0.028-3.2 μg/mL. However, to non-target honeybee receptor, this special nitro or butenolide group of four neonicotinoids was no longer only binding to the non-selective β subunit of receptor. Three among four neonicotinoids like flupyradifurone, guadipyr and ethoxythiagua as a case of low bee-toxicity reported in the previous study, were happened to display an exactly inverted binding orientation, namely, an unusual electronegative group captured another selective α subunit. However, this high bee-toxicity imidacloprid remained one conserved conformation into the non-selective β subunit as that seen from aphid receptor. This unique molecular mechanism of selectively binding to honeybee receptor, particularly to different subunit, was proposed cautiously to be one of factor determined the distinctive bee-toxicity for four neonicotinoids. These findings on the diverse mode of action for neonicotinoids to target and non-target receptor would be helpful for on novel insecticides design with high bioactivity as well as good selectivity based on the structure of different insect nAChR.
烟碱型乙酰胆碱受体（nAChR）作为新烟碱类杀虫剂作用的一个有吸引力的靶点，近年来受到越来越多的关注。新烟碱类对nAChR的作用方式研究将为合理的分子设计提供重要指导，以进一步发现新的杀虫剂。在本研究中，将包括市售药剂吡虫啉和氟吡呋喃酮在内的四种新烟碱类化合物，以及我们实验室之前合成的两种化合物瓜地吡和乙氧基噻唑啉，分别对接至蚜虫和蜜蜂nAChR的一个假定模型中，以探究新烟碱类的结合和选择性机制。所得结果表明，传统的氢键相互作用作为主要的静电驱动力，总是赋予四种新烟碱类化合物不仅与靶标蚜虫受体结合，而且与非靶标蜜蜂受体结合的能力。四种新烟碱类化合物在蚜虫受体中几乎呈现出一致的结合构象，即一个重要的电负性硝基或丁烯内酯基团被保留，以嵌套在一个非选择性的β亚基中。对棉蚜的生物测定研究也证实了它们具有优异的杀虫活性，LC值低至0.028 - 3.2μg/mL。然而，对于非靶标蜜蜂受体，四种新烟碱类化合物的这个特殊硝基或丁烯内酯基团不再仅与受体的非选择性β亚基结合。四种新烟碱类化合物中的三种，如氟吡呋喃酮、瓜地吡和乙氧基噻唑啉，在前一项研究中被报道为低蜜蜂毒性的例子，恰好呈现出完全相反的结合方向，即一个不寻常的电负性基团捕获了另一个选择性的α亚基。然而，这种高蜜蜂毒性的吡虫啉在非选择性β亚基中保持与蚜虫受体中所见的一种保守构象。谨慎地提出，这种与蜜蜂受体，特别是与不同亚基选择性结合的独特分子机制是决定四种新烟碱类化合物不同蜜蜂毒性的因素之一。这些关于新烟碱类对靶标和非靶标受体不同作用方式的发现，将有助于基于不同昆虫nAChR的结构设计具有高生物活性和良好选择性的新型杀虫剂。
