新型活性分子与靶酶相互作用机制研究驱动生态型除草剂的创新和发展

he development of ecological herbicides with low resistance and easy degradation is important in theory and has great value in application. This is a major direction in herbicide development. In the support of National Natural Science Foundation of China, we have discovered a class of high active compound with novel structure, which has completely different backbone structure with commercial herbicide compounds. Most importantly, it has great potential to become a high active compound for rice herbicide. In the dose of 75 g ai/ha, this compound can effectively control weeds in rice field and is safe to rice. In this project, we will rely on above discovery to study molecular mechanism of weed target enzyme inhibition by this compound, characterize compound interaction sites of enzyme, and determine its resistance factor and anti-resistant mechanism. Based on above work, we will apply knowledge and technologies, including target enzyme, molecular docking, effective organic synthesis, and degradation mechanism, to further evaluate and optimize the compound, to develop a new class of ecological herbicide with low resistance and easy degradation. It will form a new developing strategy of ecological herbicide, which is driving by interaction mechanism between active molecule and target enzyme. It will also significantly stimulate the research and development of innovative herbicides in China.

低抗性、易降解的生态型除草剂的研究和开发具有重要的理论意义和实际应用价值，是除草剂研究和发展的重要方向。在国家自然科学基金资助下，我们发现了一类高活性化合物，其分子骨架和已商品化的除草剂完全不同，结构具有新颖性；更重要的是发现了一个可以发展为稻田除草剂的高活性化合物，它在75 g ai/ha剂量下能有效控制稻田主要杂草，且对水稻安全。本项目将在上述研究和发现的基础上，进一步开展该类高活性化合物和靶酶的分子作用机制研究，从分子层次上解析这类高活性化合物和靶酶的作用区域及作用位点，阐明它的抗性效率及可能的反抗性作用机制；在此基础上，大胆采用对靶设计-分子对接-高效合成-降解机理研究的新策略，深入评估和优化该类化合物，开发成一种低抗性、易降解的生态型除草剂。形成以活性分子与靶酶互作机制研究驱动的生态型除草剂开发新策略，促进我国新农药创制的发展。

低抗性、易降解的生态型除草剂的研究和开发具有重要的理论意义和实际应用价值，是除草剂研究和发展的重要方向。首先，本项目开展了高效合成方法研究，构建了一种溶剂控制的发散式合成嘧啶衍生物的方法；发展了一种以二甲基亚砜为硫源，一步在苯环上导入甲硫基-羟基的双官能团化新反应，并用于构建含硫嘧啶分子库。其次，表达和纯化了野生型和十一种突变型拟南芥乙酰羟酸合成酶（AtAHAS），建立了乙酰羟酸合成酶抑制剂的筛选平台。发现化合物5和 4c的靶标是AHAS，它们对W574L突变型的乙酰羟酸合成酶都具有良好的抑制活性，表明这两个化合物有潜力被开发成为新型的反抗性除草剂。运用分子动力学模拟和圆二色光谱的方法对化合物与酶结合的作用机制进行了初步探索。研究结果为设计生态型除草剂提供了新的策略。