MDMX公司
平方毫米
小分子
抗癌药
生物
药物发现
配体(生物化学)
生物物理学
计算生物学
药理学
癌症研究
生物化学
药品
受体
基因
作者
Grzegorz M Popowicz,Anna Z. Czarna,Siglinde Wolf,Kan Wang,Wei Wang,Alexander Dömling,Tad A. Holak
出处
期刊:Cell Cycle
[Informa]
日期:2010-03-15
卷期号:9 (6): 1104-1111
被引量:202
摘要
Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.
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