靶向GLP-1R、DPP-IV的新型抗II型糖尿病药物设计研究

Both glucagon-like peptide 1 receptor (GLP-1 R) and dipeptidyl peptidase IV (DPP-IV) are important targets in terms of the treatment of type 2 diabetes. GLP-1R agonists and DPP-IV inhibitors showed good curative effects and small side effects, so they are the most promising therapeutics for the treatment of type 2 diabetes. However, there has been no research report about the drug that can work on these two proteins at the same time. The applicant of the project boldly explored and tried to find some compounds that can not only activate GLP-1R but also inhibit the activity of DPP-IV, which will greatly improve the therapeutic effect of type 2 diabetes. So, the purpose of the project is to investigate the interacting mechanisms of both agonist-GLP-1R and inhibitor-DPP-IV, and to design and develop dual ligands of GLP-1R agonism and DPP-IV inhibitory activity by means of molecular modeling, computer-aided drug design, chemical synthesis and pharmacology. Also, the structural optimization will be performed based on the skeletons of our lead compounds confirmed by bioassay aiming at finding novel drug leads. Our research might promote the study on novel drugs for the treatment of type 2 diabetes. Therefore, the implementation of this project is of not only important scientific significance, but also practical significance and the broad application prospect.

胰高血糖素样肽-1受体(GLP-1R)和二肽基肽酶IV (DPP-IV)都是II型糖尿病的重要治疗靶标，GLP-1R激动剂或DPP-IV抑制剂对II型糖尿病均具有良好的治疗效果，且副作用小，是最具前景的II型糖尿病治疗药物。但目前还没有同时作用于这两个靶点的药物研究报道。项目申请者进行大胆的探索与尝试，试图找到既能激动GLP-1R，同时又能抑制DPP-IV活性的化合物，这将大大提高II型糖尿病的治疗效果。为此，项目申请者拟综合运用分子模拟、计算机辅助药物设计、化学合成、药理学等方法，研究激动剂-GLP-1R以及抑制剂-DPP-IV之间的相互作用机理，开发GLP-1R激动剂、DPP-IV抑制剂双重配体，并针对其药理作用进行结构优化，以发现新型抗II型糖尿病药物先导化合物。其结果将把抗II型糖尿病的药物研究推进一大步，因此，本项目的实施不但具有重大的科学意义，而且具有宽广的现实意义和应用前景。

II型糖尿病占糖尿病患者总数的90-95%，由于其长期性的严重并发症，给患者带来了极大的痛苦。胰高血糖素样肽-1受体（GLP-1R）和二肽基肽酶IV（DPP-IV）都是II型糖尿病的重要治疗靶标，GLP-1R激动剂或DPP-IV抑制剂对II型糖尿病均具有良好的治疗效果，且副作用小，是最具前景的II型糖尿病治疗药物。但目前还没有同时作用于这两个靶点的药物研究报道。我们进行大胆的探索与尝试，探究激动剂–GLP-1R及抑制剂–DPP-IV的相互作用机理，并在此基础上，尝试开发GLP-1R激动剂、DPP-IV抑制剂双重配体。通过分子动力学模拟及结合自由能计算等方法，我们阐明了激动剂–GLP-1R及抑制剂–DPP-IV的相互作用机理，为靶向GLP-1R或DPP-IV的药物设计和结构改造提供了重要理论指导和线索。通过虚拟筛选、结构改造及生物活性测试等手段，最终得到对GLP-1R有激动活性的新结构化合物4个；发现和改造得到24个结构新颖且有较高活性的DPP-IV抑制剂。这些研究结果把靶向GLP-1R、DPP-IV的新型抗II型糖尿病药物研究推进了一大步，为靶向这两个蛋白的抗II型糖尿病药物发现奠定了坚实的基础。