Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening
Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening
复制标题
DOI：
10.1016/j.bmc.2007.07.016
复制
发表时间：
2007-11-01
影响因子：
3.5
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
--
作者：
Hirayama, Kazunori;Aoki, Shunsuke;Wada, Keiji
UCH-L3（泛素C-末端水解酶-L3）是一种去泛素化酶，是泛素-蛋白酶体系统的一种组分，已知参与程序性细胞死亡。先前的高通量药物筛选研究将靛红衍生物鉴定为UCH-L3抑制剂。在这项研究中，我们试图确定一种新的抑制剂与不同的结构基础。我们使用人类UCH-L3晶体结构数据（PDB代码; IXD 3）和虚拟化合物库（ChemBridge CNS-Set）进行了基于结构的药物设计（SBDD），其中包括32，799种化学物质。采用DOCK软件（一次筛选）和GOLD软件（二次筛选）两步虚拟筛选法，共鉴定出10个GOLD评分大于60的化合物。为了解决这些化合物是否表现出对UCH-L3的去泛素化活性的抑制作用，我们使用泛素-7-氨基-4-甲基香豆素（Ub-AMC）作为底物进行了所有酶测定。因此，我们确定了三种具有类似基本二氢吡咯骨架的化合物作为UCH-L3抑制剂。这些新的化合物可能有助于UCH-L3功能的研究，以及UCH-L3相关疾病的药物开发。(C)2007爱思唯尔有限公司保留所有权利。
UCH-L3 (ubiquitin C-terminal hydrolase-L3) is a de-ubiquitinating enzyme that is a component of the ubiquitin-proteasome system and known to be involved in programmed cell death. A previous study of high-throughput drug screening identified an isatin derivative as a UCH-L3 inhibitor. In this study, we attempted to identify a novel inhibitor with a different structural basis. We performed in silico structure-based drug design (SBDD) using human UCH-L3 crystal structure data (PDB code; IXD3) and the virtual compound library (ChemBridge CNS-Set), which includes 32,799 chemicals. By a two-step virtual screening method using DOCK software (first screening) and GOLD software (second screening), we identified 10 compounds with GOLD scores of over 60. To address whether these compounds exhibit an inhibitory effect oil the de-ubiquitinating activity of UCH-L3, we performed all enzymatic assay using ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) as the substrate. As a result, we identified three compounds with similar basic dihydro-pyrrole skeletons as UCH-L3 inhibitors. These novel compounds may be useful for the research of UCH-L3 function, and in drug development for UCH-L3-associated diseases. (C) 2007 Elsevier Ltd. All rights reserved.