Abstract
The development of bioactive small molecules as probes or drug candidates requires discovery platforms that enable access to chemical diversity and can quickly reveal new ligands for a target of interest. Within the past 15 years, DNA-encoded library (DEL) technology has matured into a widely used platform for small-molecule discovery, yielding a wide variety of bioactive ligands for many therapeutically relevant targets. DELs offer many advantages compared with traditional screening methods, including efficiency of screening, easily multiplexed targets and library selections, minimized resources needed to evaluate an entire DEL and large library sizes. This Review provides accounts of recently described small molecules discovered from DELs, including their initial identification, optimization and validation of biological properties including suitability for clinical applications.
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Acknowledgements
The authors thank A. Vieira for her valuable assistance and input. They thank M. O’Reilly for contributing DNA-encoded library architecture and selection figures. This work was supported by NIH R35 GM118062 and the Howard Hughes Medical Institute.
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A.A.P. and D.R.L. are co-inventors on patent applications on DNA-encoded libraries and their applications. D.R.L. is a consultant and co-founder of Exo Therapeutics, a company that uses DNA-encoded libraries.
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Protein Data Bank: https://www.rcsb.org/
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Peterson, A.A., Liu, D.R. Small-molecule discovery through DNA-encoded libraries. Nat Rev Drug Discov 22, 699–722 (2023). https://doi.org/10.1038/s41573-023-00713-6
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DOI: https://doi.org/10.1038/s41573-023-00713-6
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