基于天然产物新型α-葡萄糖苷酶抑制剂的发现及作用机理研究

α-glucosidase is an important target for diabetes treatment and pro-drug research, the widespread use of α-glucosidase inhibition drugs is limited because of the gastrointestinal side effects. Pentacyclic triterpenoids are a kind of low toxicity, high efficiency, with special natural product skeleton small molecules. A wide range of basic studies are mainly on anti-inflammatory, protect liver, etc. Only few study of pentacyclic triterpenoids and its derivatives focus on anti-diabetic and their mechanism. Based on our previous study, three pentacyclic triterpenoids are treated as start material in this proposal: firstly, the three-dimensional structure database of the diabetic target biomolecules will be constructed; secondly, based on the theoretical calculation, the target pentacyclic triterpenoids derivatives and our previous compounds will be analyzed by MOE or SYBYL software through high-throughput targets virtual screening, to optimize the structures of pentacyclic triterpenoids in theory; thirdly, the potential hypoglycemic atoms or groups are introduced to the structure of pentacyclic triterpenoids to obtain series potential target compounds. And their biological activity will be validated at the level of molecular, cellular, enzyme and animal. This proposal presents the interdisciplinary combination, which will provide the theory instruction and experimental basis for research and development of new α-glucosidase inhibitor.

α-葡萄糖苷酶是糖尿病治疗和药物研发的重要靶点，该靶点药物胃肠道副作用限制其广泛使用。而五环三萜是一类低毒、高效，具有特殊天然产物骨架的小分子，其在抗炎、保肝护肝等有大量研究，但在抗糖尿病方面报道较少，作用机制尚需厘清。基于前期研究，本项目以五环三萜类化合物为物质基础，拟通过以糖尿病治疗靶点生物大分子三维结构来构建靶点库；以理论计算为依据，在分子水平上对目标三萜衍生物治疗糖尿病的靶点效应进行分析，通过MOE或SYBYL软件进行高通量多靶点虚拟筛选，使得三萜化合物的结构在理论上进行优化；基于上述分子模拟，通过化学修饰在三萜母核结构中引入具有潜在降糖活性的原子或基团，得到多系列新型目标三萜衍生物，并在分子、细胞、酶和动物水平予以验证。本项目在虚拟筛选和实验相结合的条件下体现多学科交叉，可为新型α-葡萄糖苷酶抑制剂的研究提供理论和实验依据。

α-葡萄糖苷酶是糖尿病治疗和药物研发的重要靶点，该靶点药物胃肠道副作用限制其广泛使用。而五环三萜是一类低毒、高效，具有特殊天然产物骨架的小分子，其在抗炎、保肝护肝等有大量研究，但在抗糖尿病方面报道较少，作用机制尚需厘清。基于前期研究，本项目以五环三萜类化合物为物质基础，拟通过以糖尿病治疗靶点生物大分子三维结构来构建靶点库；以理论计算为依据，在分子水平上对目标三萜衍生物治疗糖尿病的靶点效应进行分析，通过MOE或SYBYL软件进行高通量多靶点虚拟筛选，使得三萜化合物的结构在理论上进行优化；基于上述分子模拟，通过化学修饰在三萜母核结构中引入具有潜在降糖活性的原子或基团，得到多系列新型目标三萜衍生物，并在分子、细胞、酶和动物水平予以验证。本项目在虚拟筛选和实验相结合的条件下体现多学科交叉，可为新型α-葡萄糖苷酶抑制剂的研究提供理论和实验依据。