蜕皮激素受体EcR（ecdysone receptor）通过与内源蜕皮激素结合调控昆虫的蜕皮、变态和繁殖。蜕皮激动剂竞争性结合EcR，持续存在诱导产生致死性蜕皮，并且EcR仅存在于无脊椎动物体内，对哺乳动物安全，是设计和开发新型绿色杀虫剂的重要靶标。申请人利用虚拟筛选结合活性评价已成功发现了多个结构新颖且具有较好结合活性和广谱杀虫活性的蜕皮激动剂。本研究项目拟在申请人前期研究的基础上，充分考虑EcR蛋白柔性对虚拟筛选结果的影响，采用机器学习方法构建基于靶标多构象及MM/GBSA结合自由能分解的整合虚拟筛选模型，并利用构建的模型进行多层级高精度的虚拟筛选，结合有机合成、离体及活体杀虫活性测试发现活性好、作用谱广、结构新颖的蜕皮激动剂先导，为新型绿色杀虫剂的开发奠定坚实的基础。

The hormonal action of 20E is exerted through activation of the ecdysone receptor (EcR), an invertebrate nuclear receptor responsible for transcriptional regulation of molting. Based on this mode of action, ecdysone agonists targeting EcR have been developed as insect growth regulators (IGRs), which are pesticides for control of harmful arthropods. The applicant has identified several promising EcR agonists with broader spectrum of insecticidal activity and novel chemical structures by virtual screening and biological assays. In order to take the influences of protein flexibility for EcR on the virtual screening into a full consideration, the project plans to develop a virtual screening strategy based on multiple receptor conformations by integrating the predictions from molecular docking and MM/GBSA binding free energy decomposition through machine-learning approaches. The well-validated integrated screening strategy is employed to screen large compound libraries. The candidate compounds are submitted to molecular dynamics simulations and binding free energy calculations. According to the results of binding free energy calculations and structural clustering, some potential EcR agonists will be chosen for biological testing. The goal of the project is to identify promising EcR agonists with good activity, broad spectrum and novel scaffolds, aiming at the development of new pesticides for combating pest.