新型琥珀酸-泛醌氧化还原酶抑制剂的分子设计、合成及杀菌活性研究

项目名称： 新型琥珀酸-泛醌氧化还原酶抑制剂的分子设计、合成及杀菌活性研究

项目编号： No.21272092

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 朱晓磊

作者单位： 华中师范大学

项目金额： 80万元

中文摘要： 琥珀酸-泛醌氧化还原酶是当前最重要的农用杀菌剂作用靶标之一，针对该靶标的商品化农用杀菌剂已有近20种。但由于长期的、反复的大规模应用，病原菌针对该类杀菌剂的抗药性发展也日益迅速。本项目以文献报道的SQR晶体结构及本课题组已经建立的SQR抑制剂筛选方法为基础，系统研究商品化抑制剂与SQR相互作用的分子机制及构效关系，明确对抑制剂结合起关键作用的氨基酸残基，采用申请人所在课题组前期发展的药效团连接碎片虚拟筛选分子设计策略开展分子设计研究，培养高活性分子与SQR相结合的复合物晶体并进行结构解析，并采用申请人所在课题组前期发展的计算突变扫描方法对所得到的高活性分子进行抗性风险预测，力争通过分子设计-合成-活性筛选-抗性预测的研究循环，最终获得2-3个具有低抗性风险的新型SQR杀菌剂先导化合物。该项目的实施将进一步丰富完善农药分子设计理论，为我国的新农药创制基础研究作出积极贡献。

中文关键词： 琥珀酸脱氢酶；药物分子设计；虚拟筛选；；

英文摘要： Succinate ubiquinone oxidoreductase (SQR) has been identified as one of the most important targets for about 20 commerical fungicides. The long-term and frequent use of SQR fungicides has resulted in many pathogen species developing resistance to these fungicides. In this project, the molecular mechanism between inhibitor and SQR and the structure-activity relationship of inhibitors would be studied systematicly based on the crystal structure of SQR and the bioassay method established previously. And the key amino residues for binding of SQR inhibitors would be found out. After that, the pharmacophore-linked fragment virtual screening (PFVS) method developed by our lab would be used to design novel SQR inhibitors with higher activity. With high active inhibitors as probes, we are going to the crystallographic studies of SQR-inhibitor crystal complex. Furthermore, the prediction of resistance risk would be performed for high active compounds by computational mutation scanning (CMS) method developed in our team before. Based on the research cycle composed of molecular design, synthesis, bioassay and the resistance risk prediction, we strive to obtain 2-3 lead compounds with low resistance risk. Hopefully, the implementation of this project will enrich the molecular design theory in pesticide field, leading an inte

英文关键词： Succinate dehydrogenase；drug design；virtual screen；；