DNA-Encoded Library Technology in Drug Discovery

DNA-Encoded Library (DEL) technology has transformed early-stage drug discovery by enabling the simultaneous synthesis and screening of millions to billions of small molecules in a single pooled experiment. Each compound in a DEL bears a unique DNA tag that records its synthetic history, allowing rapid identification of binders through simple DNA sequencing rather than labour-intensive deconvolution. The core workflow comprises split-and-pool synthesis on DNA, application of DNA-compatible reaction chemistries to build structural diversity, and affinity selection against biological targets. Hits recovered from target binding are decoded by high-throughput sequencing and validated off-DNA. Recent advances have focused on expanding the range of on-DNA chemistries, improving library fidelity and tag stability, and integrating machine learning to predict productive building blocks. DEL platforms now routinely yield novel chemotypes against challenging targets such as enzymes, protein–protein interactions and membrane receptors. The scalability, cost-efficiency and speed of DEL screening render it a global tool for lead discovery, target validation and the rapid optimisation of structure–activity relationships.

Research from Nature Portfolio

One recent study introduced a trio-pharmacophore DEL constructed by self-assembly of three pre-purified sub-libraries, enabling simultaneous selection of two fragments and their linking moiety. This approach maintained drug-like molecular weights while facilitating de novo discovery against proteolytic enzymes and matrix metalloproteases. A foundational work developed a chemical ligation method for constructing a 334-million member library by cycloaddition of oligonucleotide tags, leading to the identification of potent soluble epoxide hydrolase inhibitors. Earlier, an automated parallel DEL screening platform was used to assess ligandability across over one hundred bacterial protein targets, demonstrating that the number of encoded binders correlates with target tractability and guiding prioritisation in antibacterial drug discovery.

DNA-Encoded Library Technology in Drug Discovery publication trend

The graph below shows the total number of articles in dna-encoded library technology in drug discovery across all publications each year (not limited to Nature Index journals).

Technical terms

DNA-encoded library (DEL): A collection of small molecules each tagged with a unique DNA sequence that encodes its synthetic history and enables pooled screening.

Split-and-pool synthesis: A combinatorial approach in which reaction mixtures are divided and recombined iteratively to generate large, diverse libraries on DNA tags.

On-DNA chemistry: Chemical transformations performed on DNA-conjugated substrates under conditions that preserve DNA sequence integrity.

Affinity selection: The enrichment of library members that bind to a specific biological target, followed by recovery and decoding of bound ligands.

Pharmacophore: The set of structural features of a molecule required for optimal interaction with a biological target.

Ligandability: The inherent potential of a biomolecular target to bind drug-like ligands with high affinity and specificity.

References

1. Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers. Nature Communications (2023).
2. Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library. Scientific Reports (2015).
3. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. Nature Communications (2017).
4. DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output. RSC Advances (2021).
5. DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions. Advanced Science (2019).
6. Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery. Molecules (2019).