新型HPPD抑制剂的设计、合成及除草活性研究

对羟基苯基丙酮酸双氧化酶（HPPD）抑制剂具有广谱、高效、环境相容性好，鲜有抗性的报道等优点，是除草剂研究的热点领域之一。不同来源的HPPD结构差异较大，但目前大部分商品化抑制剂对人源HPPD表现出比植物源HPPD更好的抑制活性。如何设计合成出对植物源HPPD具有高抑制活性的高选择性新型除草剂是一个具有理论和实际意义的研究课题。本项目拟将有机合成技术、分子生物学技术与计算机模拟技术进行有机结合。通过深入研究不同类型商品化药剂与不同来源HPPD的相互作用，找出与植物源HPPD结合口袋中可能与抑制剂发生特异性相互作用的氨基酸残基，揭示选择性产生的分子机制。在此基础上，采用药效团连接碎片虚拟筛选方法设计合成选择性对AtHPPD具有较高抑制活性的分子，力争获得1-2个结构新颖、选择性更高、并具有广谱高效除草活性的HPPD抑制剂分子。该项目将为进一步开发新型HPPD抑制型除草剂奠定坚实的基础。

4-Hydroxyphenylpyruvate dioxygenase (HPPD) recently has received much interest because of its broad spectrum, high efficiency, good environmental compatibility, almost no resistance to the reports and other advantages. Research shows that, there is a great difference between the different sources of HPPD structure, but most of the current commercial inhibitors showed inhibitory activity on hHPPD better than on AtHPPD. Therefore, the design and synthesis of new highly selective HPPD herbicide has great significance. Therefore, the interactions between various herbicides and different sources of HPPD will be investigated systematically, using the combination of the techniques of organize synthesis, molecular biology and molecular modeling, to find out some residues in plant pocket of HPPD, which can make specific interaction with the inhibitors. As a result, the rules of interactions between HPPD and various herbicides will be summarized to understand the molecular mechanism of selective generation, and then design and synthesis of novel selective inhibitor molecules with high inhibitory activity on AtHPPD through Pharmacophore-linked Fragment Virtual Screening （PFVS）method. The project will lay a foundation of further development of new high selectivity HPPD inhibitor.