毛冬青PA类五环三萜选择性拮抗ADP的机制和构效研究

项目名称： 毛冬青PA类五环三萜选择性拮抗ADP的机制和构效研究

项目编号： No.81503232

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 林丽萍

作者单位： 南京中医药大学

项目金额： 18万元

中文摘要： ADP受体拮抗剂是临床重要的抗血小板聚集药物。前期研究发现毛冬青五环三萜母核Pomolic acid (PA)具有显著的选择性拮抗ADP诱导的血小板聚集活性(解离常数Kb=15.4 nM)。受此启发，本项目拟通过制备PA分子探针，进行靶点垂钓，从而鉴定PA作用的具体靶点。在此基础上，以毛冬青为研究对象，运用UPLC/Q-TOF/MS技术结合活性导向分离，高效快速地获得新的PA类五环三萜活性成分；利用3D-QSAR导向合成制备系列新的PA类五环三萜衍生物；进而采用ADP受体抑制活性为指标，结合3D-QSAR技术综合评价上述系列PA类五环三萜拮抗ADP的构效关系；发现1-2个高效、安全的先导化合物，为研究和开发毛冬青五环三萜ADP受体拮抗剂提供理论依据，为毛冬青植物的科学利用提供新用途。

中文关键词： 毛冬青；五环三萜；ADP拮抗剂；分子机制；构效关系

英文摘要： ADP antagonists is an important kind of antiplatelet drugs used in clinic. Inspired by the significant inhibitory effect on ADP-induced platelet aggregation (Kb of 15.4 nM) of pomolic acid (PA), a parental nucleus of triterpene from Ilex pubescens, we will focus on making reliable PA molecular probe to identify its direct target. Based on the evidence, we will continue to enrich the compounds libraries through using UPLC/Q-TOF/MS technology combined with bioassay-guided fractionation and 3D-QSAR oriented synthesis to obtained more new PA-like triterpene. Then, using the result of inhibitory activity against identified target as index, combined with the 3D-QSAR technology, the structure-activity relationship of PA-like triterpene as selectively ADP-antagonist will be evaluated comprehensively. This work is expected to find 1-2 components as lead compounds with high efficiency and low toxicity and provide the theoretical basis for the research and development of ADP antagonists from Ilex pubescens. It also will exploied a new scientific application for Ilex pubescens.

英文关键词： Ilex Pubescens;Triterpene;ADP-antagonists;Molecular Mechanism;Structure-Activity Relationship