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High-Throughput Binder Confirmation (HTBC).

Bing Xia1, Jennifer D Summerfield2

  • 1Encoded Library Technologies/NCE Molecular Discovery, R&D Medicinal Science and Technology, GlaxoSmithKline, Cambridge, MA, USA.

Methods in Molecular Biology (Clifton, N.J.)
|September 9, 2022
PubMed
Summary
This summary is machine-generated.

This study introduces a DNA-encoded library (DEL) method using cleavable linkers for rapid confirmation of small molecule binders. This approach enables high-throughput binder confirmation (HTBC) for efficient interrogation of selection results.

Keywords:
DNA-encoded library (DEL)High-throughput confirmationHit confirmationPhotocleavable linker (PCL)Tetrahydropyranyl cleavable linker (THP)

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Area of Science:

  • Biochemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • DNA-encoded libraries (DELs) are powerful tools for identifying small molecule binders.
  • Hit confirmation is a critical bottleneck in DEL screening.
  • Efficient methods are needed to validate binders identified through DEL selections.

Purpose of the Study:

  • To describe a DNA-encoded library "recipe" approach for hit confirmation.
  • To present on-DNA cleavable linker strategies for releasing small molecules.
  • To enable direct analysis of released small molecules using mass spectrometry.

Main Methods:

  • Utilizing on-DNA cleavable linkers for small molecule release.
  • Employing direct mass spectrometry (AS-MS) for binder identification.
  • Integrating automation for a high-throughput binder confirmation (HTBC) platform.

Main Results:

  • Demonstration of a DEL "recipe" approach for hit confirmation.
  • Reporting two distinct on-DNA strategies for releasing small molecules.
  • Successful identification of binders from released small-molecule mixtures.

Conclusions:

  • The described DEL approach facilitates efficient and high-throughput binder confirmation.
  • On-DNA cleavable linkers coupled with AS-MS streamline the validation process.
  • This platform enhances the interrogation of DEL selection results.