局部组织糖皮质激素（GC）水平的异常升高会导致胰岛素抵抗，而胰岛素抵抗是2型糖尿病发病的中心环节。11β-HSD1是GC的主要代谢调节酶，大量实验表明其异常高活性会引起局部组织GC水平的升高，进而导致胰岛素抵抗。因此，11β-HSD1的高选择性抑制剂有望成为治疗2型糖尿病的新策略。申请人在前期工作中发现中药枸骨代谢一种极为罕见的18,19-secoursane皂苷，并首次发现该类化合物对11β-HSD1具有显著的选择性抑制活性，IC50值达到33nM。基于此，本项目拟以枸骨为研究对象，首先利用生物活性和LC-MS导向的精准分离手段从枸骨中定向获得18,19-secoursane皂苷及其类似物，总结初步构效关系；然后，对活性分子与11β-HSD1进行分子对接研究，获取分子/酶结合模式，继而以此为基础进行结构修饰和构效关系研究，通过活性评价最终获得11β-HSD1的高选择性高效抑制。

Abnormal elevation of local tissue glucocorticoids (GC) can lead to insulin resistance, which is central to the onset of type 2 diabetes.11β-HSD1 is an important metabolic enzyme of GC, whose high activity will cause elevated GC levels in local tissues, and thus leading to insulin resistance. Therefore, the high selective inhibitor of 11β-HSD1 is expected to be a noval strategy for the treatment of type 2 diabetes. In the previous study, the applicant found that the plant Ilex cornuta metabolites a severely rare skeleton of 18,19-secoursane saponins, which showed significant selective inhibitory activity against 11β-HSD1, with IC50 value reaching 33 nM. Based on this, the project is to take Ilex cornuta as the research object, firstly using the approach named "precise separation" guided by biological activity and LC-MS to obtain 18,19-secoursane saponins and their analogues, following by the summary of preliminary structure-activity relationship. Then, molecular docking was performed on the active molecules and 11β-HSD1 to obtain the molecular/enzyme docking patterns, on which performing on the study of structural modification and structure-activity relationship were based. Finally, an effective inhibitor with high selectivity was obtained by the activity evaluation.