Environmental enrichment abilities and chronic sub-lethal effects on non-target organisms caused by neonicotinoid insecticides (neonics) have been challenging issues for environmental pollution. In other words, the renewal of insecticides, especially the research of green substitutes, is one of the best ways to protect the environment and non-target organisms. In this research, a complete design and screening system for green substitutes of neonics was established through the contour map, homology modeling, molecular docking, and molecular dynamics. Contour maps were constructed to obtain the substituted sites and groups, and the results revealed that introducing large, negative/positive or hydrophobic groups can reduce the enrichment abilities of neonics. Using Compound 18 as a template, 58 derivatives with lower enrichment abilities were designed (decreased by 0.55%-57.42%). Then, human health risks were assessed based on multimedia exposure model of pollutants, and the HI values of five derivatives were found to be <1 and the RI values were <1 × 10⁻⁶, indicating that the non-carcinogenic risks of the neonics derivatives were completely acceptable, and the carcinogenic risks were negligible. Furthermore, the multi-selective toxicity of five derivatives in farmland ecosystems was studied using homology modeling and molecular docking, and Derivative-1, Derivative-3, Derivative-10, and Derivative-56 showed multi-selective toxicity on farmland ecosystems. Specifically, the toxicity effects on pests and grubs were enhanced (increased by 1.44%-12.58%), whereas the chronic sublethal effects on bees and earthworms were reduced (decreased by 0.29%-27.18%). Finally, the damage to soybean leaves caused by four derivatives was analyzed by molecular dynamics, and the solvent accessible surface area of the above four derivatives was found to be smaller than that of Compound 18, indicating that the derivatives decomposed more easily in soybean crops, thus reducing the damage to the soybean’s leaf surface. This study provides a significance reference in designing green substitutes for neonics to protect the environment and ecosystem.

由新烟碱类杀虫剂（neonics）引起的环境富集能力和对非目标生物的慢性亚致死作用一直是环境污染的难题。换句话说，更新杀虫剂，特别是绿色替代品的研究，是保护环境和非目标生物的最佳方法之一。在这项研究中，通过等高线图，同源性建模，分子对接和分子动力学，建立了完整的设计和筛选新体系的绿色替代品。构造等高线图以获得取代的位点和基团，结果表明，引入大的，负/正或疏水基团会降低新电子的富集能力。以化合物18为模板，设计了58种富集能力较低的衍生物（降低了0.55％-57.42％）。然后，基于污染物的多媒体暴露模型评估人类健康风险，并发现五个导数的HI值<1，RI值<1×10 ^-6，表明该新衍生物的非致癌风险是完全可以接受的，致癌风险可以忽略。此外，使用同源性建模和分子对接研究了五种衍生物在农田生态系统中的多选择毒性，Derivative-1，Derivative-3，Derivative-10和Derivative-56对农田生态系统表现出多选择毒性。具体而言，对害虫和g的毒性作用增强（增加了1.44％-12.58％），而对蜜蜂和worm的慢性亚致死作用减小了（减少了0.29％-27.18％）。最后，通过分子动力学分析了四种衍生物对大豆叶片的损害，发现上述四种衍生物的溶剂可及表面积小于化合物18的表面积。表明该衍生物在大豆作物中更容易分解，从而减少了对大豆叶表面的损害。这项研究为设计绿色环保替代品提供了重要的参考，以保护环境和生态系统。