基于LC-MS/MS分子网络对诃子类藏药中抗糖尿病活性成分的定向挖掘及其作用机制研究

糖尿病是严重危害人类社会的主要健康问题，研发高效、低毒副作用的新型抗糖尿病药物十分迫切。诃子是一种重要的民族药，被誉为藏药之王，也是印度传统药、中药以及许多少数民族常用药，与毛诃子等被藏医常用于治疗糖尿病，但药效物质基础至今不清。本项目以HPLC、LC-MS和LC-MS/MS为主要手段，通过GNPS平台及前期已有化合物库和数据库，建立诃子类藏药及其民间代用品的分子网络。并以此为指导下，结合活性初筛，采用现代各种分离技术和谱学、化学等方法，快速锁定并分离鉴定诃子类藏药中多样化的目标Scaffolds，阐明这类重要民族药的化学物质基础和分子多样性。同时，采用体内外以及靶向导向与表型导向并用的抗糖尿病活性筛选模型，从诃子类藏药中发现一系列抗糖尿病活性化合物，通过构效关系探讨和作用机制研究，发现新的抗糖尿病先导分子，为诃子类藏药的民族药用和深入挖掘利用，以及抗糖尿病药物的研发提供科学依据和基础。

Diabetes is a global health problem harmful seriously to the human health. It is urgent to develop new anti-diabetes drugs, with higher therapeutic, but lower toxic and side effects. Terminalia chebula, known as the King of Tibetan medicine, is an important ethno-medicine also used mostly by the Indian Ayurvedic medicine, traditional Chinese medicine and many ethnic medicines, and has been used frequently to the treatment of diabetes mellitus, together with another plants, e.g., T. bellerica, however, the bioactive chemical principles are so far not well investigated. Based on our previous study, this project is going to establish firstly a molecular networking of Terminalia spp. and its subsituents, by HPLC, LC-MS and LC-MS/MS techniques through the GNPS spectral database together with our established chemical bank and data. Furthermore, a series target chemical scaffolds will be isolated by various chromatography from Terminalia spp. and its subsituents, and determined by modern spectroscopic and chemical methods, in order to explore the chemical substances and molecular diversity of this important ethnomedicine. At the same time, based on the traditional uses and modern pharmacological study, a series of anti-diabetic chemical constituents will be discovered by the established in vitro and in vivo target oriented and phenotypic oriented anti-diabetic bioassays. On the basis of the structure and activity relationship as well as their active mechanism, it is hopeful to identify a couple of anti-diabetic leading compounds, laying a foundation for the scientific evidence corresponding for the traditional uses and further reasonable utilization of these important ethnomedicine, as well as the development of new and safer anti-diabetic drugs.