杂草抗性成为制约乙酰羟酸合成酶（AHAS）抑制型除草剂可持续发展的关键。全世界已报道的144种AHAS抗性杂草中，有70种是由于AHAS的P197突变而导致的。因此，P197突变型杂草分布最广且危害最严重，如何规避P197突变产生的抗性是针对AHAS设计合成新型除草剂必须面临的挑战。本项目拟综合运用分子模拟、合成及化学生物学等技术，深入研究除草剂与AHAS及P197突变体之间的相互作用，揭示P197突变的分子机制。在此基础上，采用虚拟筛选方法发现对P197突变型AHAS具有活性的苗头化合物，进而开展结构优化、抗性风险、合成及生物活性研究。同时分离鉴定各种P197突变型杂草，并建立相关筛选体系。力争通过"设计－抗性风险－合成－生物活性"的研究循环，最终获得1-2个具有高活性、低抗性风险、结构骨架新颖的除草先导化合物。该项目的实施将进一步推动反抗性农药分子设计研究，为我国农药创制做出积极贡献。

The sustainable development of Acetohydroxyacid synthase (AHAS) inhibiting herbicides were circumscribed by resistant weeds. Among 144 kinds of AHAS resistant weeds, 70 kinds were induced by mutations of P197, which were the most widely distributed and harmful classes. Hence, how to avoid resistance induced by P197 mutations is of great challenge in the design of novel AHAS inhibiting herbicide. The techniques of molecular modeling, organic synthesis, chemical biology, and so on will be applied to study the interaction and resistance mechanism between AHAS inhibiting herbicides and P197 mutants. On this basis, hit compounds with bioactivity to P197 mutants will be discovered by virtual screening. In addition, structural optimization, resistance risk prediction, synthesis, and bioassay will be performed. To establish herbicide screening system focused on resistant weeds, P197 mutant weeds will be isolated and identified. Finally, 1-2 herbicide leads with high activity, low resistance risk, and novel structure will be obtained through the research cycle of "Design-Resistance risk-Synthesis- Bioactivity". The implementation of this project will not only promote the development of anti-resistance pesticide design, but make positive contributions for the basic research of pesticide discovery in our country.