基于天然产物分子碎片重组设计的新型HPPD抑制剂的合成及分子作用机制研究

抗性杂草爆发性的增长已成为现代农业可持续发展所面临的一个关键挑战，而创制新型超高效除草剂是解决这一挑战的根本途径。以对羟基苯丙酮酸双加氧酶(HPPD)为靶标的除草剂具有高效、广谱、低毒、不易产生抗性等优点。本项目针对作物田中杂草抗性及除草剂使用中的安全性问题，提出以HPPD为靶标酶，利用虚拟筛选与天然产物碎片重组技术相结合，设计新型HPPD抑制类除草剂，开展结构修饰，通过“设计―合成―筛选―除草活性―田间试验”多次循环，筛选出1-2个高活性候选化合物。并综合运用分子模拟、化学生物学等技术，深入研究抑制剂分子与HPPD之间的分子作用机制。通过上述研究以期获得新型绿色HPPD抑制类除草剂候选化合物，为我国自主开发绿色、高效、安全、广谱、环境友好的HPPD抑制类除草剂提供理论研究基础，并为解决目前杂草抗性问题及除草剂对作物的安全性问题提供有效的解决途径。

The explosive growth of resistant weeds has become a key challenge for the sustainable development of modern agriculture, and the creation of new ultra-efficient herbicides is the fundamental way to solve this challenge. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors shared the advantages of high efficiency, low toxicity, high crop safety and low resistance. This study is to find a good way to solve the weed resistance and the safety issues to crops in the use of herbicides. Herein a series of novel HPPD inhibitors were designed by using natural product fragment recombination technology with HPPD as the target enzyme. Novel herbicidal candidates with better activity were selected via the multiple cycles of "design-synthesis-high-throughput screening-herbicidal activity-field test". The molecular mechanism between inhibitor and HPPD was studied by means of molecular simulation, chemical biology and other technologies. This research provides preliminary theoretical research for independent development of high efficiency, safety, broad-spectrum, and environmentally friendly HPPD inhibitors, and provides an effective solution to the weed resistance and herbicide safety issues.