以琥珀酸脱氢酶为靶标的新型杀虫剂的分子设计与合成

The increasingly serious problem of resistance demands that we must develop insecticides with new mode of action. Succinate dehydrogenase (SDH)-targeted insecticides shows novel mechanism of action and no cross-resistance to existing acaricides. There are significant differences on the structure of SDH between the insect and other species. So far, the crystal structure of insect SDH has not been reported. Therefore, structure-based rational design of SDH-targeted insecticides is a challenging research topic and has practical as well as theoretical importance. In this project, the 3D structure of insect SDH would be constructed by homology modeling firstly. Meanwhile, the extracted and purified insect SDH was used to develop enzyme-based assay for SDH. And then, a rational and predictive 3D structure of insect SDH would be constructed with combined strategy of theoretical prediction and experimental confirmation. The acrylonitrile-based and amide-based SDH inhibitor was used as lead scaffold to carry out Pharmacophore-linked Fragment Virtual Screening (PFVS) respectively. Finally, 1-2 novel insecticide leads with efficient and low poison will be discovered by the "molecular design, synthesis, bioactivity screening and pesticide-likeness optimization" research process cycle. This project ultimately seeks to promote the research of SDH-targeted insecticides and innovative pesticides research & development in China.

昆虫抗药性的迅猛发展迫切需求具有新颖作用机制的杀虫剂新品种问世。以线粒体琥珀酸脱氢酶（SDH）为靶标的杀虫剂具有作用机制新颖、与现有品种无交互抗性等特点。昆虫SDH与其他种属SDH的结构差异显著，而目前尚未见昆虫SDH晶体结构的报道。因此，基于SDH三维结构设计新型杀虫剂是一个具有重要理论与现实意义又富有挑战的研究课题。为此，本项目首先采用同源模建技术建立昆虫SDH的三维结构。与此同时，提取纯化昆虫SDH并建立抑制剂筛选方法。通过理论与实验相结合，建立具有较强预测能力的、可靠的SDH三维结构。在此基础上，分别以丙烯腈类和酰胺类SDH抑制剂为先导结构，开展药效团连接碎片虚拟筛选，通过“分子设计-有机合成-活性测试-类农药性优化”的研究循环，力争获得1~2个高效、低毒的杀虫剂新先导结构。本项目的实施将为以SDH为靶标的新型杀虫剂的发现提供新思路，为我国新农药创制基础研究作出积极贡献。

昆虫抗药性的迅猛发展迫切需求具有新颖作用机制的杀虫剂新品种问世。以线粒体琥珀酸脱氢酶（SDH）为靶标的杀虫剂具有作用机制新颖、与现有品种无交互抗性等特点。昆虫SDH与其他种属SDH的结构差异显著，而目前尚未见昆虫SDH晶体结构的报道。因此，基于SDH三维结构设计新型杀虫剂是一个具有重要理论与现实意义又富有挑战的研究课题。为此，本项目首先采用同源模建技术建立了具有较强预测能力的、可靠的昆虫SDH的三维结构。在此基础上，分别以丙烯腈类和酰胺类SDH抑制剂为先导结构，开展了药效团连接碎片虚拟筛选。通过“分子设计-有机合成-活性测试-类农药性优化”的研究循环，合成了150余个全新化合物，从中筛选获得含环氧活性片段的苯基噻唑和苯基恶唑两类杀虫活性优异的新先导结构，为开发新型SDH靶向杀虫剂奠定了一定的基础。