靶向代谢型谷氨酸受体8变构调节位点的3DShapeSim药物发现与镇痛作用研究

项目名称： 靶向代谢型谷氨酸受体8变构调节位点的3DShapeSim药物发现与镇痛作用研究

项目编号： No.81502988

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： 艾妮

作者单位： 浙江大学

项目金额： 17.9万元

中文摘要： 神经病理性疼痛是一种由神经系统原发损害或功能障碍引起的影响全世界约6-8%人口的慢性疼痛疾病。目前仅有7种治疗神经病理性疼痛药物被批准且疗效有限、副作用显著,因此新药开发极为重要。基于III组代谢性谷氨酸受体8(mGluR8）在病理状态下疼痛信息传导的重要作用及申请人前期工作发现的mGluR8正向变构剂，本项目提出一种靶向mGluR8变构调节位点的多层次药物发现策略，从3DShapeSim出发，着重研究具有相似活性形状的分子群，集成多种计算方法评价其与mGluR8受体结合力及血脑屏障通透性，通过体外和疾病动物模型实验平台进一步筛选活性高、类药性佳的mGluR8变构调节剂且验证其体内药效，综合运用分子生物学、药理学方法考察mGluR8变构剂的亚型选择性及镇痛机制。本项目的研究有助于发现成药性高的治疗神经病理性疼痛先导化合物，为mGluR8神经药理学研究提供新的工具药并具有着重要的临床意义。

中文关键词： 药物发现；变构调节剂；代谢型谷氨酸受体8；神经病理性疼痛；3DShapeSim

英文摘要： Neuropathic pain is chronic pain conditions caused by a primary neurological damage or dysfunction that is estimated to inflence 6-8% of populations around the world. Only seven drugs are approved for treating neuropathic pain and they are associated with limited efficacy and significant side effects. It is extremely important to develop new drugs for this disease. Literatures have demonstrated group III metabotropic glutamate receptor 8 (mGluR8) plays an important role in signal transduction of pain in pathological conditions and my previous work also have identified a positive allosteric modulator.Based on these findings, this project aims to establish a multi-level screening system targeting allosteric site of mGluR8. 3DShapeSim is used first to identify the small molecule cluser with similar three-dimensional shape with known mGluR8 allosteric modulator. Mutiple computational approaches are integrated to evaluate the binding affinity and blood brain barrier permeability of these molecules. Application of this screening system will result in mGluR8 allosteric modulators with high activity and excellent drug-like properties, which then can be developed as lead compounds for the treatment of neuropathic pain. We also will investigate selectivity accross mGluR family and elucidate possible mechanisms of action for these modulators, which can be used as tool drugs to study neurological functions of mGluR8 and would show great clinical potential.

英文关键词： drug discovery;allosteric modulator;metabotropic glutamate receptor 8 ;neuropathic pain;3DShapeSim