Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Bioorg Med Chem Lett. 2021 Aug 15;46:128120. doi: 10.1016/j.bmcl.2021.128120. Epub 2021 May 17.
Triflumezopyrim (TFM) is a new mesoionic insecticide developed by DuPont. Like other neonicotinoid insecticides, it binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR), but the binding mode has not been reported. Nicotinic acetylcholine binding proteins (nAChBPs) are ideal alternative structure for nAChRs. In this study, molecular docking, molecular dynamics (MD) simulations, binding free energy calculation, and per-residue binding free energy decomposition were used to study the binding modes of TFM and other 12 mesoionic insecticides. By comparing the binding free energy and the insecticidal activity, it was found that the sub-pocket around the benzyl group of the mesoionic insecticide is the key area for maintaining its activity, which is composed of A: Val116, A: Met124, A: Ile126, B: Trp155 and B: Val156. In order to verify the druggability of the sub-pocket, a series of iminosydnone compounds were designed and synthesized based on the structure of the sub-pocket. The lethality rate of compound 1 against Mythimna separata were 100% at 500 mg/L. Our research provides a basis for designing new mesoionic insecticides based on structure.
三氟醚吡咯（TFM）是杜邦公司开发的一种新型中杂环杀虫剂。与其他新烟碱类杀虫剂一样，它与烟碱型乙酰胆碱受体（nAChR）的正位点结合，但结合模式尚未报道。烟碱型乙酰胆碱结合蛋白（nAChBPs）是 nAChRs 的理想替代结构。在这项研究中，采用分子对接、分子动力学（MD）模拟、结合自由能计算和残基结合自由能分解的方法，研究了 TFM 和其他 12 种中杂环杀虫剂的结合模式。通过比较结合自由能和杀虫活性，发现中杂环杀虫剂苄基周围的亚口袋是维持其活性的关键区域，由 A：Val116、A：Met124、A：Ile126、B：Trp155 和 B：Val156 组成。为了验证亚口袋的成药性，根据亚口袋的结构设计并合成了一系列亚胺基噻二唑类化合物。化合物 1 对粘虫的致死率在 500mg/L 时达到 100%。我们的研究为基于结构设计新型中杂环杀虫剂提供了依据。
