College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China; The State Key Laboratory of Regional Optimisation of Energy System, North China Electric Power University, Beijing 102206, China.
Ecotoxicol Environ Saf. 2018 Nov 30;164:467-473. doi: 10.1016/j.ecoenv.2018.08.055. Epub 2018 Aug 23.
A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established based on the molecular structures and the negative logarithm of experimental lethal concentration 50 values (pLC) of neonicotinoid insecticides. Then, the mechanisms of bi-directional selective toxic effects and drug resistance were determined using homology modeling and molecular docking analyses. The results of the model showed that the 1-, 2-, 4-, and 12- positions of neonicotinoid insecticides strongly affected their toxicity, and that the introduction of bulky or electropositive groups at these positions could increase the pLC values. Using Compound 19 as a template, we designed 37 derivatives with greater toxicity (increased by 0.04-11.45%). Among them, 20 derivatives had bioconcentrations lower than that of Compound 19 (reduced by 0.38-147.88%). Further screening of Compound 19 and the 20 derivatives mentioned above by homology modeling and acetylcholine receptors (AChRs) molecular docking analyses showed that 10 derivatives had bi-directional selective toxic effects against pests and bees. Further docking analyses of Compound 19 and these 10 derivatives identified that Derivative-33 showed decreased docking with superoxide dismutase (SOD) and glutathione S transferase (GST) in pests and enhanced docking with these enzymes in bees, indicating bi-directional selective resistance for pests and bees. Accordingly, Derivative-33 was selected as a new insecticide with high toxicity to pests and low toxicity to bees (bi-directional selective toxicity), low resistance in pest populations, and high resistance in bee populations. This study provides valuable reference data and will be useful for the development of strategies to produce new environmentally friendly pesticides.
建立了基于新烟碱类杀虫剂分子结构和实验致死浓度 50 的负对数（pLC）的三维定量构效关系（3D-QSAR）模型。然后，通过同源建模和分子对接分析，确定了双向选择毒性作用和抗药性的机制。模型结果表明，新烟碱类杀虫剂的 1-、2-、4-和 12-位强烈影响其毒性，在这些位置引入大体积或正电性基团可以增加 pLC 值。以化合物 19 为模板，设计了 37 种毒性更大的衍生物（增加了 0.04-11.45%）。其中，20 种衍生物的生物浓缩度低于化合物 19（降低了 0.38-147.88%）。通过同源建模和乙酰胆碱受体（AChRs）分子对接分析进一步筛选化合物 19 和上述 20 种衍生物，发现 10 种衍生物对害虫和蜜蜂具有双向选择毒性作用。进一步对接分析化合物 19 和这 10 种衍生物，发现衍生物-33 与害虫中超氧化物歧化酶（SOD）和谷胱甘肽 S 转移酶（GST）的对接减少，而与蜜蜂中这些酶的对接增强，表明对害虫和蜜蜂具有双向选择抗性。因此，选择衍生物-33 作为一种新型杀虫剂，对害虫具有高毒性，对蜜蜂的毒性低（双向选择毒性），在害虫种群中抗性低，在蜜蜂种群中抗性高。本研究为开发新型环保农药提供了有价值的参考数据，并将有助于制定新的环保农药发展策略。
