琥珀酸脱氢酶与酰胺类抑制剂的相互作用研究及反抗性杀菌剂分子设计

琥珀酸脱氢酶（SDH）是重要的杀菌剂靶标之一，但是抗性问题一直是困扰SDH进一步发展的最大障碍。如何规避和克服抗性是新型SDH抑制剂设计所面临的巨大挑战。前期我们已经获得了一类高活性先导化合物Y18909系列，该类化合物具有潜在的反抗性特性。因此，本项目拟以Y18909系列化合物与靶标的作用机制为起点，结合分子模拟方法分析Y18909系列化合物与商品化SDH杀菌剂作用机制的差异性，同时采用基因敲除重组的方法构建酿酒酵母中SDH的突变体，采用离体驯化的方法获得病原菌抗性菌株，进行抗性机制研究，随后采用分子模拟方法构建SDH体系专属的打分函数，进行虚拟筛选，期望找到2-3个对环境友好、低抗性和高活性的新型SDH抑制剂先导化合物，为新农药创制贡献力量。

Succinate dehydrogenase was one of most important fungicide targets. But the resistance has always been the biggest obstacle to the further decelopment of SDH. How to circumvent and overcome resistance is a huge challenge in the design of new SDH inhibitors. In our preveious study, we have obtained a series of highly active lead compound (Y18909 series), which showed potential resistance characteristeric. Therefore, this project plans to start with the inhibition mechanism of Y18909 series compounds. And then combining with the molecular modeling, the inhibition difference between Y18909 series and commerical fungicides was analyzed. In addition, the resistance mechanism was done by construction of SDH mutants in saccharomyces cerevisiae by gene knockout recombination and pathogen acclimation method to obtain pathogen resistant strains. Meanwhile, the special score for SDH would be constructed based on our compounds. Finally, the virtual screening was done based on the sepcial SDH score. We strive to obtain 2-3 lead compounds, which was low resistance and high active compound. We would lay the foundation for the development of new fungicides.