Rational Design of Small-Molecule Inhibitors for 尾-Catenin/T-Cell Factor Protein鈥揚rotein Interactions by Bioisostere Replacement

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• 作者：Binxun Yu ; Zheng Huang ; Min Zhang ; Darren R. Dillard ; Haitao Ji
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：March 15, 2013
• 年：2013
• 卷：8
• 期：3
• 页码：524-529
• 全文大小：347K
• 年卷期：v.8,no.3(March 15, 2013)
• ISSN：1554-8937

文摘

A new hot spot-based design strategy using bioisostere replacement is reported to rationally design nonpeptidic small-molecule inhibitors for protein鈥損rotein interactions. This method is applied to design new potent inhibitors for 尾-catenin/T-cell factor (Tcf) interactions. Three hot spot regions of Tcf for binding to 尾-catenin were quantitatively evaluated; the key binding elements around K435 and K508 of 尾-catenin were derived; a bioisostere library was used to generate new fragments that can match the proposed critical binding elements. The most potent inhibitor, with a molecular weight of 230, has a K_d of 0.531 渭M for binding to 尾-catenin and a K_i of 3.14 渭M to completely disrupt 尾-catenin/Tcf interactions. The binding mode of the designed inhibitors was validated by the site-directed mutagenesis and structure鈥揳ctivity relationship (SAR) studies. This study provides a new approach to design new small-molecule inhibitors that bind to 尾-catenin and effectively disrupt 尾-catenin/Tcf interactions specific for canonical Wnt signaling.