獐牙菜属促胰岛功能修复与糖代谢作用的抗糖尿病小分子天然产物筛选与机制研究

The Swertia is a kind of traditional medicine for treating diabetes, and its chemical constituents and hypoglycemic activities have been systemically studied. However, due to various factors, the key mechanisms and the anti-diabetic substance basis of Swertia medicinal plants are still unclear. Accordingly, this project focuses on the establishment of anti-diabetic substances basis for the Swertia medicinal plants. The potential anti-diabetic molecules with islet restoration and glucoregulation effects will be screened by structured-based virtual ligand screening, and their mechanisms will be investigated and elucidated with in vitro and in vivo bio-assay models. Then, the anti-diabetic functions of Swertia medicinal plants with multi-components and multi-target effects will be evaluated by using uniform design-high throughput screening method. It will greatly benefit the clarification of the relationship among anti-diabetic activity, chemical composition and drug targets. This project will provide new thoughts for the research of the substance basis of traditional Chinese medicine and their kindred plants, along with the discovery of lead compounds.

獐牙菜属药用植物常被用于糖尿病的治疗，其化学成分和降血糖作用已有大量研究，但由于受多种因素的限制，其抗糖尿病的物质基础及作用机制还不真正清楚。本项目拟在前期研究的基础上，分别建立獐牙菜属小分子天然产物和糖代谢-胰岛功能修复相关靶点蛋白三维结构数据库，引入计算机模拟分子对接和微量热泳动等新技术，选择促胰岛功能修复和糖脂代谢相关的作用靶点，先行对化合物库的成分进行活性预测，然后通过均匀设计-高通量筛选方法，利用与效应靶点相关的体内外药理模型评价化合物或组合物的药效与作用机制，阐明獐牙菜属药用植物抗糖尿病传统功效-天然产物库-多成分多靶点作用-药效物质基础之间的关系，以期为多成分、多靶点、大样本的现代中药筛选与先导化合物的发现提供新思路。

本研究建立獐牙菜属小分子天然产物化合物库，包含113种实体化合物，基本覆盖了该属主要结构类型的化合物，具有较好的代表性；建立了糖代谢-胰岛功能修复相关靶点三维结构数据库，满足了两大功能对该化合物库中化合物的活性筛选；分别运用计算机软件模拟分子对接和微量热涌动技术，预测了促胰岛功能修复和糖代谢相关的作用靶点及活性化合物，结果发现与胰岛功能和糖代谢关系最为密切的靶点分别是双底物特异性酪氨酸磷酸化激酶（DYRK1A）和醛糖还原酶（Aldose reductase，AR）；然后通过酶活性测定和INS-1胰岛β细胞模型分别评价化合物对胰岛β细胞增值、胰岛素分泌和糖代谢的影响；然后利用与效应靶点相关的体内药理模型评价化合物的药效与作用机制，结果发现獐牙菜属化合物去甲基雏菊叶龙胆酮（Demethylbellidifolin，DMB）可能是一种新的安全高效的DYRK1A酶和AR酶共同的抑制剂。该发现阐明了獐牙菜属药用植物抗糖尿病传统功效-天然产物库-多成分多靶点-药效物质基础之间的关系，具有重要的理论和应用价值。.本成果发表科学论文7篇，授权中国发明专利1项，培养博士研究生3名，硕士研究生1名。