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Competitive Genomic Screens of Barcoded Yeast Libraries
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Beyond protein binding: recent advances in screening DNA-encoded libraries.

Thomas Kodadek1, Nicholas G Paciaroni1, Madeline Balzarini1

  • 1Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. kodadek@scripps.edu.

Chemical Communications (Cambridge, England)
|October 22, 2019
PubMed
Summary

DNA-encoded library (DEL) screening is a key technique for discovering drug molecules. Novel DEL assay formats now enable more complex screening beyond simple binding, including selectivity, enzyme inhibition, and organocatalyst identification.

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • DNA-encoded library (DEL) screening is a powerful technology for identifying small molecule ligands.
  • Traditional DEL screening primarily relies on simple binding assays against protein targets.
  • Recent advancements have expanded DEL capabilities beyond basic binding interactions.

Purpose of the Study:

  • To review novel DNA-encoded library (DEL) screening formats.
  • To highlight DEL applications beyond simple binding assays.
  • To discuss current challenges and future directions in DEL assay development.

Main Methods:

  • Incubation of DELs with target molecules (typically proteins).
  • Washing to remove non-specific binders.
  • Amplification and deep sequencing of DNA tags to identify bound ligands.
  • Implementation of specialized assay formats for selectivity, enzyme inhibition, and organocatalysis.

Main Results:

  • Demonstration of DELs' utility in complex screening paradigms.
  • Successful application of DELs for identifying selective binders, enzyme inhibitors, and organocatalysts.
  • Identification of new assay formats expanding the scope of DEL technology.

Conclusions:

  • DEL screening is evolving beyond simple binding assays.
  • Novel DEL formats offer enhanced capabilities for drug and probe discovery.
  • Addressing remaining challenges is crucial for further advancing DEL technology.