基于晶体结构的DPP-4和AT1受体双靶点调节剂先导化合物发现与抗糖尿病肾病作用研究

糖尿病肾病（DN）是糖尿病最常见的并发症，目前尚无特效治疗药物。致病因素复杂是当前DN药物治疗的瓶颈，针对多种致病因素的DPP-4和AT1双靶点调节剂具有成为新型DN治疗药物的潜力。课题组前期发现了多个DPP-4/AT1双靶点调节剂，DPP-4活性和临床使用药物相当，但是未找到双靶点活性均强的先导物。本课题基于DPP-4和AT1受体晶体结构、前期的构效关系研究以及分子对接结合模式提出双靶点调节剂的关键药效团模型，基于该模型，利用基于结构的药物设计原理与骨架跃迁原理、拼合原理和生物电子等排原理设计多样性的化合物库，再通过虚拟筛选，化学合成获得目标化合物，最后在受体水平、细胞水平和动物水平评估抗糖尿病肾病作用并探讨作用机制，以期开发出具有抗DN的DPP-4/AT1活性均显著的双重调节剂先导物。我们应用多靶点药物策略探究治疗DN的新思路，可为研发新型抗DN药物提供科学依据。

Diabetic nephropathy (DN) is the most common complication of diabetes. Current treatments cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. Multi-target therapeutics with their various pleiotropic effects have become new trend of drug discovery. Dual modulators of DPP-4 and AT1 receptor have potential to be new therapeutic agents for DN. In previous studies, we have identified some hit compounds with preferable DPP-4 but weak AT1 activities, thus further optimization is needed to improve the AT1 activities. In this project, based on the crystal structure of DPP-4 and AT1 receptors, combined with the systematically molecular docking and structure-activity relationships studies, a key pharmacophore model of dual modulators was developed, and then novel diverse compound libraries with the characteristics of pharmacophore were constructed by using structure-based drug design, combined with scaffold hopping, hybridization principle and bioisosterism strategies. After virtual screening, chemical synthesis, and biological evaluations and mechanism studies at different levels, novel lead compounds of dual DPP-4/AT1 modulator with excellent DPP-4 and AT1 activities will be achieved, expected to possess anti-DN activity in vitro/in vivo. The project tried to apply the multi-target drug strategy to complex metabolic diseases for discovery of new therapeutic agents of DN, which can provide scientific evidence for developing new drugs for the treatment of DN.