Rapid Identification of Keap1-Nrf2 Small-Molecule Inhibitors through Structure-Based Virtual Screening and Hit-Based Substructure Search

被引：133

作者：

Zhuang, Chunlin ^{[1
,2
]}

Narayanapillai, Sreekanth ^{[1
]}

Zhang, Wannian ^{[2
]}

Sham, Yuk Yin ^{[3
]}

Xing, Chengguo ^{[1
]}

机构：

[1] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA

[2] Second Mil Med Univ, Dept Med Chem, Shanghai 200433, Peoples R China

[3] Univ Minnesota, Ctr Drug Design, Minneapolis, MN 55455 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 03期

关键词：

PROTEIN-PROTEIN INTERACTION; FLUORESCENCE POLARIZATION; NRF2; DISCOVERY; STRESS; NEH2; OPTIMIZATION; INDUCERS; BINDING; DOMAIN;

D O I：

10.1021/jm4017174

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

In this study, rapid structure-based virtual screening and hit-based substructure search were utilized to identify small molecules that disrupt the interaction of Keap1-Nrf2. Special emphasis was placed toward maximizing the exploration of chemical diversity of the initial hits while economically establishing informative structure activity relationship (SAR) of novel scaffolds. Our most potent noncovalent inhibitor exhibits three times improved cellular activation in Nrf2 activation than the most active noncovalent Keap1 inhibitor known to date.

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收藏

页码：1121 / 1126

页数：6

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