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DNA-encoded chemistry: enabling the deeper sampling of chemical space

Nature Reviews Drug Discovery volume 16, pages 131–147 (2017)Cite this article

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This article has been updated

Key Points

  • DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods.

  • DNA-encoded chemical library technology involves the creation of large mixtures of small molecules that are encoded with sequences or single-stranded or double-stranded DNA. High-affinity hits from such mixtures are identifiable by sequencing the DNA tags associated with each compound.

  • DNA-encoded library technology began with a publication by Brenner and Lerner in 1992. The technology has subsequently evolved to be practised by several large pharmaceutical and biotechnology companies.

  • DNA-directed synthesis is a related approach. In this method, the specificity of DNA base pairing serves for both encoding and synthesis.

  • DNA-encoded library synthesis as it is currently practised is based on reactions that are tolerant to water.

  • The creation of hundreds of millions of DNA-encoded library compounds is less expensive and more feasible than assembling a library of single compounds on milligram scale.

Abstract

DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces. This Review provides an overview of the development and applications of DNA-encoded chemistry, highlighting the challenges and future directions for the use of this technology.

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Figure 1: Different DNA-encoded library technologies.
Figure 2: Building block availability analysis by functional group.
Figure 3: Cartoon of one round of affinity-mediated selection.
Figure 4: Various representations of selection outputs.

Change history

  • 30 January 2017

    The details of reference 119 were incorrect and there were also some minor typographical errors. These errors have been corrected in the online version of the article.

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Author notes

  1. Robert A. Goodnow Jr

    Present address: Present address: Pharmaron, Inc., Boston, Massachusetts 02451, USA.,

Authors and Affiliations

  1. Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Waltham, 02451, Massachusetts, USA

    Robert A. Goodnow Jr

  2. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, 4033, Switzerland

    Christoph E. Dumelin

  3. X-Chem, Waltham, 02453, Massachusetts, USA

    Anthony D. Keefe

Authors
  1. Robert A. Goodnow Jr
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  2. Christoph E. Dumelin
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  3. Anthony D. Keefe
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Corresponding author

Correspondence to Robert A. Goodnow Jr.

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Competing interests

At the time of writing this manuscript R.A.G. was an Executive Director at AstraZeneca. C.E.D. is an investigator at Novartis Pharma, and A.D.K. is a Director at X-Chem.

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DATABASES

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Glossary

Lead

A hit compound that has been characterized in terms of its drug-like properties and is likely to be a therapeutically useful starting point for improvements in potency, selectivity and pharmacokinetic profile.

High-throughput screening

(HTS). An assay of many compounds in parallel, often by automated means.

Hits

Compounds identified in a primary screen that upon off-DNA resynthesis show reproducible biochemical activity, which is confirmed in an orthogonal assay.

Split-and-pool synthesis

A combinatorial chemistry practice for creating large numbers of compounds. After the separate reaction of a first set of reagents with a common chemical transformation, the products are pooled together, resulting in a mixture of the products. This mixture is then re-arrayed for another round of separate synthesis, followed by pooling, resulting in the combination of all possible products of the two sets of building blocks.

DNA-encoded chemistry

(DEC). Encoded chemistry with encoded information stored in DNA sequences.

DNA-encoded library

(DEL). A collection of variants with distinguishing characteristics encoded in DNA.

Affinity-mediated selection

Enrichment for binding to a target, usually via target immobilization.

PCR amplification

The use of a template-dependent thermostable polymerase enzyme to amplify DNA through recursive cycles of primer binding, primer extension and thermal denaturation.

Off-DNA resynthesis

The resynthesis of compounds identified in a primary screen for the purposes of assessing their biochemical or biophysical activity in the absence of DNA.

DNA encoding

The establishment of a defined relationship between DNA sequence and chemical history.

Building blocks

Chemical reagents containing at least one reactive handle.

DNA tags

Specific sequences of DNA used to encode a specified chemical step.

Encoded self-assembled chemistry

Molecular fragments that are held in co-proximity via the hybridization of complementary DNA.

DEAE sepharose

Sepharose beads covalently linked to diethylaminoethyl groups for the reversible capture of DNA.

Disynthon

A compound library member resulting from the combination of two types of building block.

Rule of 5

A compound is deemed compliant to the Lipinski 'rule of 5' if its molecular weight is not greater than 500 Da, if its logP is not greater than 5 and if its counts of hydrogen bond donors and acceptors are not greater than 5 and 10, respectively

Fragment-based lead discovery

Discovery of near leads through the assembly of small fragments that bind in a highly efficient manner.

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Goodnow, R., Dumelin, C. & Keefe, A. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat Rev Drug Discov 16, 131–147 (2017). https://doi.org/10.1038/nrd.2016.213

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