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

Edith 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 Westen, Tiemen J. Wendel, Sylvie M. Noordermeer, Sebastian Böcker () and Sebastian Pomplun ()
Additional contact information
Edith Nol: Leiden University
Nils Alexander Haupt: Friedrich Schiller University Jena
Qing Qing Gao: Leiden University
Benthe A. M. Smit: Leiden University
Martin Andre Hoffmann: Bright Giant GmbH
Martin Engler-Lukajewski: Bright Giant GmbH
Marcus Ludwig: Bright Giant GmbH
Sean McKenna: Leiden University
J. Miguel Mata: Leiden University
Olivier J. M. Béquignon: Leiden University
Gerard Westen: Leiden University
Tiemen J. Wendel: Oncode Institute
Sylvie M. Noordermeer: Oncode Institute
Sebastian Böcker: Friedrich Schiller University Jena
Sebastian Pomplun: Leiden University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65282-1

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