基于EcR/USP结构的新型IGRs先导化合物的生物合理设计

项目名称： 基于EcR/USP结构的新型IGRs先导化合物的生物合理设计

项目编号： No.20802089

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 化学工业

项目作者： 张莉

作者单位： 中国农业大学

项目金额： 18万元

中文摘要： 发现全新结构的先导化合物是新农药原始创新的核心。本项目基于高活性双酰肼类化合物和蜕皮激素受体（EcR/USP）与不同配体形成的复合物的晶体结构，采用计算机辅助药物设计方法，进行了具有蜕皮激素活性的全新结构的化合物的设计、合成及生物活性测试。基于QSAR、3D-QSAR结果，合成了80个结构新颖的含呋喃环的双酰肼类化合物，部分化合物有较好的杀虫活性。首次构建了受体药效团模型。基于配体药效团模型和受体药效团模型进行Maybridge化合物库的虚拟筛选，得到9个候选化合物。对VS-008进行了结构优化，合成了12个未见报道的化合物。对小菜蛾杀虫实验结果表明，部分化合物显示出典型的昆虫生长调节剂的作用特点，可能是潜在的新型IGRs先导化合物。

中文关键词： EcR/USP；蜕皮激素；药效团；虚拟筛选；有机合成

英文摘要： To discover novel lead compounds is the core of the new pesticide discovery.Based on the structures of diacylhydrazine analogs and the crystal structure of the complex of EcR/USP and different ligands, the design, synthesis and bioassay of novel structures with molting hormone activity were carried out by using the computer-aided drug design method in this research.Based on the results of QSAR and 3D-QSAR study, 80 novel diacylhydrazide with furan ring were synthesized. Some compounds showed excellent insecticide activity in vivo. The receptor pharmacophore model was firstly constructed. Based on the above ligand model and receptor model, the virtual screening was studied with Maybridge database. And 9 candidate molecules were chosen. In the basis of active comformation of diacylhydrazines, the compound named VS-008 was modified. 12 novel compounds were synthesized and tested their bioactivity to Diamondback moth (Plutella xylostella) in vivo. The result shows that some compounds act the same features as insect growth regulators. This kind compound may be a potiental novel IGRs lead.

英文关键词： EcR/USP; ecdysteroid hormone; pharmacophore model; virtual screening; synthesis