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

An Erratum to this article was published on 01 October 2009

This article has been updated

Abstract

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.

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Figure 1
Figure 2: Selection of DEL-A against p38 MAPK.
Figure 3: Selection of DEL-A against Aurora A kinase.
Figure 4: Selection of DEL-B against p38 MAPK.

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Change history

  • 17 September 2009

    In the version of this article initially published, the IC50 values in the table in Figure 3c were listed as nM instead of μM. The error has been corrected in the HTML and PDF versions of the article.

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Correspondence to Barry A Morgan.

Supplementary information

Supplementary Text and Figures

Supplementary Methods (PDF 2038 kb)

Supplementary Dataset 1

DEL-A Synthon List (XLS 124 kb)

Supplementary Dataset 2

DEL-B Synthon List (XLS 195 kb)

Supplementary Dataset 3

DEL-A Selection - p38 MAPK (XLS 547 kb)

Supplementary Dataset 4

DEL-A Selection - Aurora A, Method A (XLS 31 kb)

Supplementary Dataset 5

DEL-A Selection - Aurora A, Method B (XLS 20 kb)

Supplementary Dataset 6

DEL-B Selection - p38 MAPK (XLS 24 kb)

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Clark, M., Acharya, R., Arico-Muendel, C. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat Chem Biol 5, 647–654 (2009). https://doi.org/10.1038/nchembio.211

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