Identification of small molecular inhibitors for Ero1p by structure-based virtual screening
Identification of small molecular inhibitors for Ero1p by structure-based virtual screening
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通过基于结构的虚拟筛选鉴定 Ero1p 小分子抑制剂
DOI：
10.1016/j.bmcl.2010.12.129
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发表时间：
2011-02-15
影响因子：
2.7
通讯作者：
Tang, Yun
中科院分区：
文献类型：
--
作者：
Chu, Yanyan;Chen, Xianjun;Tang, Yun
Ero1p以分子氧作为其优选的末端电子受体，通过与蛋白质二硫键异构酶相互作用促进二硫键形成。Ero1p功能障碍导致未折叠蛋白反应的强烈激活和细胞活力的显著丧失。然而，Ero1p的适度衰减改善了在内质网应激中受到高水平蛋白质错误折叠挑战的酵母的适应性。因此，Ero1p的部分抑制具有重要意义。本文采用基于对接的虚拟筛选方法对Ero1p抑制剂进行了筛选，从81个具有微摩尔抑制作用的化合物中成功筛选出12个化合物。特别是，6个命中显示出显著的效力，IC 50 < 30 μ M，并具有成为先导化合物的前景。然后分析了相互作用模式，为进一步的铅优化。(c)2010爱思唯尔有限公司版权所有。
Ero1p, using molecular oxygen as its preferred terminal electron acceptor, promotes disulfide bond formation by interaction with protein disulfide isomerase. Dysfunction of Ero1p leads to strong activation of the unfolded protein response and marked loss of cell viability. However, modest attenuation of Ero1p improves the fitness of yeast challenged with high levels of protein misfolding in their endoplasmic reticulum stress. Partial inhibition of Ero1p is hence of great significance. In the present paper, a docking-based virtual screening method was performed to identify inhibitors of Ero1p and 12 hits were successfully obtained from 81 purchased compounds with micromolar inhibition against Ero1p. Particularly, six of the hits demonstrated remarkable potency with IC50 < 30 mu M and held the prospect of becoming lead compounds. Then the interaction modes were analyzed for further lead optimization. (c) 2010 Elsevier Ltd. All rights reserved.