nNOS-Capon偶联抑制剂的筛选、合成和活性评价  

Screen,synthesis and activity evaluation of nNOS-Capon coupling inhibitor

作　　者：张玉霞 朱志颖 蒋南 秦亚娟 厉廷有[1,2] ZHANG Yuxia;ZHU Zhiying;JIANG Nan;QIN Yajuan;LI Tingyou(Department of Medicinal Chemistry,Nanjing Medical University,Nanjing 211166,China;Jiangsu Province Collaborative Innovation Center of Cardiovascular Translational Medicine,Nanjing 211166,China)

机构地区：[1]南京医科大学药物化学系,南京211166 [2]江苏省心血管转化医学协同创新中心,南京211166

出　　处：《西北药学杂志》2020年第6期894-898,共5页Northwest Pharmaceutical Journal

基　　金：国家自然科学基金项目(编号:81574280,81803349);江苏省自然科学基金项目(编号:20171048)。

摘　　要：目的研究表明神经元型一氧化氮合酶(nNOS)的PDZ羧基末端配体(Capon)解偶联可作为抗焦虑药物研发的新靶点,本研究的目的是发现新型nNOS-Capon偶联抑制剂。方法 ZLc-002是有效的nNOS-Capon偶联抑制剂,以ZLc-002与nNOS PDZ结构域结合口袋为模板筛选已知化合物,对所得的化合物进行基于荧光偏振的生物活性评价。结果通过虚拟筛选得到4个化合物wy-1~wy-4,对发现的化合物及其类似物wy-4-N进行活性分析,发现化合物wy-2和wy-4-N在200μmol·L^(-1)时对nNOS PDZ结构域具有9%的竞争性结合活性。结论研究对nNOS-Capon偶联抑制剂的发现具有一定的指导意义。Objective Studies exhibited that neuronal nitric oxide synthase(nNOS)-carboxy-terminal PDZ ligand of nNOS(Capon)coupling can serve as a new target for developing anxiolytic drugs.The objective of the present study is to find unique nNOS PDZ domain inhibitors.Methods ZLc-002 is a potent nNOS-Capon coupling inhibitor.We utilized the binding pocket of ZLc-002 binding to nNOS PDZ domain as template to screen known-compounds,and the bioactivities of the obtained compounds were measured on the basis of fluorescence polarization.Results Through virtual screening,4 compounds wy-1-wy-4 were obtained.The activity analysis of the discovered compounds and their analogs wy-4-N showed that compounds wy-2 and wy-4-N were found to have competitive binding activity to the nNOS PDZ domain at a concentration of 200μmol·L-1(9%).Conclusion This research is instructive to develop new nNOS-Capon coupling inhibitors.

关 键 词：焦虑症 PDZ结构域 计算机筛选 nNOS-Capon偶联 

分 类 号：R914[医药卫生—药物化学]