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

Nature Communications, vol. 16, pp. 9479

Abstract

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.

Authors 15

1. Edith van der Nol Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   LACDR, Leiden University, Leiden, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

2. Nicola Haupt

   Friedrich Schiller University Jena

   Affiliation as printed

   Chair for Bioinformatics, Institute for Computer Science, Friedrich Schiller University Jena, Jena, Germany

3. Qingsong Gao Aachen

   Leiden University

   Affiliation as printed

   LACDR, Leiden University, Leiden, The Netherlands

4. Benthe A. M. Smit Aachen

   Leiden University

   Affiliation as printed

   LACDR, Leiden University, Leiden, The Netherlands

5. Martin Andre Hoffmann
   Affiliation as printed

   Bright Giant GmbH, Hans-Knöll-Straße 6, Jena, Germany

6. Martin S. Engler
   Affiliation as printed

   Bright Giant GmbH, Hans-Knöll-Straße 6, Jena, Germany

7. Marcus Ludwig
   Affiliation as printed

   Bright Giant GmbH, Hans-Knöll-Straße 6, Jena, Germany

8. Sean M. McKenna Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   LACDR, Leiden University, Leiden, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

9. J. Miguel Mata Aachen

   Leiden University · Oncode Institute

   Affiliation as printed

   LACDR, Leiden University, Leiden, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

10. Olivier J. M. Béquignon Aachen

    Leiden University

    Affiliation as printed

    LACDR, Leiden University, Leiden, The Netherlands

11. Gerard J. P. van Westen Aachen

    Leiden University

    Affiliation as printed

    LACDR, Leiden University, Leiden, The Netherlands

12. Tiemen J. Wendel Aachen Department of Human Genetics

    Leiden University Medical Center · Oncode Institute

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Oncode Institute, Utrecht, The Netherlands

13. Sylvie M. Noordermeer Aachen Department of Human Genetics

    Leiden University Medical Center · Oncode Institute

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Oncode Institute, Utrecht, The Netherlands

14. Sebastian Böcker corresponding

    Friedrich Schiller University Jena

    Affiliation as printed

    Chair for Bioinformatics, Institute for Computer Science, Friedrich Schiller University Jena, Jena, Germany. sebastian.boecker@uni-jena.de

    Chair for Bioinformatics, Institute for Computer Science, Friedrich Schiller University Jena, Jena, Germany

15. Sebastian J. Pomplun corresponding Aachen

    Leiden University · Oncode Institute

    Affiliation as printed

    LACDR, Leiden University, Leiden, The Netherlands. s.j.pomplun@lacdr.leidenuniv.nl

    Oncode Institute, Utrecht, The Netherlands. s.j.pomplun@lacdr.leidenuniv.nl

    LACDR, Leiden University, Leiden, The Netherlands

    Oncode Institute, Utrecht, The Netherlands