基于中草药天然产物的核受体靶点药物筛选及调控结构机理研究

项目名称： 基于中草药天然产物的核受体靶点药物筛选及调控结构机理研究

项目编号： No.U1405220

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 李勇

作者单位： 厦门大学

项目金额： 254万元

中文摘要： 糖尿病、肿瘤等重大疾病是一直以来影响全人类健康的重大因素。核受体配体在生理病理方面具有重要调控作用。然而，配体化合物的毒副作用是药物研发的瓶颈问题。鉴于现有中草药的相对安全有效性，其有效成分的多样性，以及其对疾病的广泛适用性，本项目将围绕闽台两地共有的中药材和天然产物资源，全面有机结合高通量药物筛选技术、结构生物学、生物化学与分子生物学、药物化学、细胞与小鼠模型的研究手段和方法，筛选对肿瘤、代谢性疾病等重大疾病有潜在疗效的以核受体为靶标的新配体药物，研究新配体化合物对疾病的疗效和药理，阐明化合物与靶标核受体的构效关系及信号转导机理，为优化、设计下一代药物提供有高度应用价值的科学依据。该项研究将会在中药有效成分药物靶标的发现和功能机理、以及中草药现代化方面做出巨大贡献，以期开发出一系列具有闽台地域优势和自主知识产权的新药。

中文关键词： 核受体；中草药；靶点药物；构效关系；功能机理

英文摘要： The growing epidemic of diabetes and cancer is one of the major health care problems in the world today. The nuclear receptors are important drug targets due to their regulation functions in physiological and also pathological processes including diabetes and cancer. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. However, clinical use of many nuclear receptor ligands is limited by a number of side effects. Chinese herbs with reduced side effects and large-scale structural diversity have become major resources for the discovery of lead compounds for new drug research. Recent studies have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products as candidates in drug discovery. Meanwhile, both drug targets and molecular mechanisms of Chinese herbs remain elusive, which hinders the further development and modernization of Chinese herbs. As such, the identification of new targets for Chinese herbs is critical for their further development..We intend to take advantage of the resources of Chinese herbs and natural products in the cross strait area including Fujian and Taiwan, combined with our research experience and strength in the study of structure–activity relationship (SAR) of nuclear receptors, in developing new drugs targeting metabolic diseases and cancer with improved potency and efficacy but reduced side effects. We will first screen for novel ligands for nuclear receptors PPAR、FXR and RAR, respectively, and then further study physiological effects of the hit compounds with focus on their molecular mechanisms and signal transduction pathway. Moreover, we plan to determine the crystal structures of the nuclear receptors complexed with these ligands and perform detailed structure–activity relationship (SAR) analysis. Our research together will reveal important mechanistic understandings for the drug functions of Chinese herbs by uncovering their targets, and also provide templates for designing highly selective and efficient nuclear receptor ligands with therapeutic potentials for the treatment of diabetes and cancer.

英文关键词： NULL