基于新靶标的除草剂创制研究是当前农药发展的迫切需要、是解决当前杂草抗性发展问题和满足环境生态高要求有效途径之一。本项目拟以植物2C-甲基赤藓糖-4-磷酸途径（MEP途径）关键酶IspD为靶标，开展基于结构的除草剂先导结构化合物的设计合成和生物活性研究。研究内容包括基于IspD靶标结构的含有疏水基团和多重氢键给体/受体杂环结构的虚拟化合物库构建和虚拟筛选、先导结构化合物的设计合成和结构优化、拟南芥靶标蛋白IspD的表达纯化和基于靶标的高通量筛选方法、化合物对模式植物抑制的活体生物活性和构效关系、基于高活性化合物为分子探针的抑制作用机理研究等。本项目研究目标是发现2-3个高活性的MEP途径IspD酶抑制剂、建立IspD酶抑制剂作用机制的研究方法。

The discovery of new herbicides based on new target proteins is the stringent need for the pesticide development, and it is also an effective route to solve the problem of herbicidal resistance development in weeds and to meet the higher requirements of environmental and ecological protein and management. This project will focus on the key target protein IspD in the 2C-methyl-d-erythritol 4-phosphate pathway (MEP) in plants, and initiate the works on the design and synthesis of lead structure compounds targeting the protein IspD using the structure-based drug discovery methodology and the bioactivity assay. Main contents in this project will include the construction of the virtual compound libraries with the structural characters containing the hydrophobic groups and the heterocycles with multiple H-bonding donors/acceptors in terms of the features of the allosteric site of IspD enzyme, the virtual high throughput bioactivity screening using the IspD crystal structure model, the design and synthesis of lead hit compounds and their structural optimization, the expression and purification of the IspD protein from the plant Arabidopsis Thaliana and the experimental high throughput bioactivity screening method based on the target protein, in vivo activity toward model plants and the structure-effect relationship, and the investigation of the action mechanism of highly bioactive lead compounds based on the molecular probe strategies. The ultimate goal of this project is the discovery of 2 or 3 lead compounds with new structures and high bioactivity as well as the establishment of the methodology for the research on the action mode of IspD target-based inhibitors.