Design, synthesis and selection of DNA-encoded small-molecule libraries

被引：527

作者：

Clark, Matthew A. ^{[1
]}

Acharya, Raksha A. ^{[1
]}

Arico-Muendel, Christopher C. ^{[1
]}

Belyanskaya, Svetlana L. ^{[1
]}

Benjamin, Dennis R. ^{[1
]}

Carlson, Neil R. ^{[1
]}

Centrella, Paolo A. ^{[1
]}

Chiu, Cynthia H. ^{[1
]}

Creaser, Steffen P. ^{[1
]}

Cuozzo, John W. ^{[1
]}

Davie, Christopher P. ^{[1
]}

Ding, Yun ^{[1
]}

Franklin, G. Joseph ^{[1
]}

Franzen, Kurt D. ^{[1
]}

Gefter, Malcolm L. ^{[1
]}

Hale, Steven P. ^{[1
]}

Hansen, Nils J. V. ^{[1
]}

Israel, David I. ^{[1
]}

Jiang, Jinwei ^{[1
]}

Kavarana, Malcolm J. ^{[1
]}

Kelley, Michael S. ^{[1
]}

Kollmann, Christopher S. ^{[1
]}

Li, Fan ^{[1
]}

Lind, Kenneth ^{[1
]}

Mataruse, Sibongile ^{[1
]}

Medeiros, Patricia F. ^{[1
]}

Messer, Jeffrey A. ^{[1
]}

Myers, Paul ^{[1
]}

O'Keefe, Heather ^{[1
]}

Oliff, Matthew C. ^{[1
]}

Rise, Cecil E. ^{[1
]}

Satz, Alexander L. ^{[1
]}

Skinner, Steven R. ^{[1
]}

Svendsen, Jennifer L. ^{[1
]}

Tang, Lujia ^{[1
]}

van Vloten, Kurt ^{[1
]}

Wagner, Richard W. ^{[1
]}

Yao, Gang ^{[1
]}

Zhao, Baoguang ^{[2
]}

Morgan, Barry A. ^{[1
]}

机构：

[1] GlaxoSmithKline, Mol Discovery Res Boston, Waltham, MA USA

[2] GlaxoSmithKline, Computat & Struct Chem, King Of Prussia, PA USA

来源：

NATURE CHEMICAL BIOLOGY | 2009年 / 5卷 / 09期

关键词：

CHEMICAL LIBRARIES; RNA DISPLAY; LIGANDS; EVOLUTION; DISCOVERY; PHAGE;

D O I：

10.1038/nchembio.211

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.

引用

页码：647 / 654

页数：8

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