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.
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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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.
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.
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.
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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