化学
DNA
G蛋白偶联受体
小分子
药物发现
计算生物学
整体膜蛋白
细胞
受体
细胞膜
膜蛋白
膜
DNA测序
细胞生物学
生物化学
生物
作者
Zining Wu,Todd L. Graybill,Xin Zeng,Michael Platchek,Jean Zhang,Vera Q. Bodmer,David D. Wisnoski,Jianghe Deng,Frank T. Coppo,Gang Yao,Alex M. Tamburino,Genaro S. Scavello,G. Joseph Franklin,Sibongile Mataruse,Katie L. Bedard,Yun Ding,Jing Chai,Jennifer D. Summerfield,Paolo A. Centrella,Jeffrey A. Messer,Andrew J. Pope,David I. Israel
标识
DOI:10.1021/acscombsci.5b00124
摘要
DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.
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