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<p>Affinity-selection platforms are powerful tools in early drug discovery, but current technologies – most notably DNA-encoded libraries (DELs) – are limited by synthesis complexity and incompatibility with nucleic acid-binding targets. We present a barcode-free self-encoded library (SEL) platform that enables direct screening of over half a million small molecules in a single experiment. SELs combine tandem mass spectrometry with custom software for automated structure annotation, eliminating the need for external tags for the identification of screening hits. We develop efficient, high-diversity synthesis protocols for a broad range of chemical scaffolds and benchmark the platform in affinity selections against carbonic anhydrase IX, identifying multiple nanomolar binders. We further apply SELs to flap endonuclease 1 (FEN1) – a disease related DNA-processing enzyme inaccessible to DELs – and discover potent inhibitors. Taken together, screening barcode-free libraries of this scale all at once represents an important development, enables access to novel target classes, and promises substantial impact on both academic and industrial early drug discovery.</p>

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Barcode-free hit discovery from massive libraries enabled by automated small molecule structure annotation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月27日

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  • Edith van der Nol,
  • Nils Alexander Haupt,
  • Qing Qing Gao,
  • Benthe A. M. Smit,
  • Martin Andre Hoffmann,
  • Martin Engler-Lukajewski,
  • Marcus Ludwig,
  • Sean McKenna,
  • J. Miguel Mata,
  • Olivier J. M. Béquignon,
  • Gerard van Westen,
  • Tiemen J. Wendel,
  • Sylvie M. Noordermeer,
  • Sebastian Böcker,
  • Sebastian Pomplun

摘要

Affinity-selection platforms are powerful tools in early drug discovery, but current technologies – most notably DNA-encoded libraries (DELs) – are limited by synthesis complexity and incompatibility with nucleic acid-binding targets. We present a barcode-free self-encoded library (SEL) platform that enables direct screening of over half a million small molecules in a single experiment. SELs combine tandem mass spectrometry with custom software for automated structure annotation, eliminating the need for external tags for the identification of screening hits. We develop efficient, high-diversity synthesis protocols for a broad range of chemical scaffolds and benchmark the platform in affinity selections against carbonic anhydrase IX, identifying multiple nanomolar binders. We further apply SELs to flap endonuclease 1 (FEN1) – a disease related DNA-processing enzyme inaccessible to DELs – and discover potent inhibitors. Taken together, screening barcode-free libraries of this scale all at once represents an important development, enables access to novel target classes, and promises substantial impact on both academic and industrial early drug discovery.