Virtual fragment screening for DNA repair inhibitors in vast chemical space

Andreas Luttens, Duc Duy Vo, Emma R. Scaletti, Elisée Wiita, Ingrid Almlöf, Olov Wallner, Jonathan Davies, Sara Košenina, Liuzhen Meng, Maeve Long, Oliver Mortusewicz, Geoffrey Masuyer, Flavio Ballante, Maurice Michel, Evert Homan, Martin Scobie, Christina Kalderén, Ulrika Warpman Berglund, Andrii V. Tarnovskiy, Dmytro S. Radchenko, Yurii S. Moroz, Jan Kihlberg, Pål Stenmark, Thomas Helleday and Jens Carlsson ()
Additional contact information
Andreas Luttens: BMC
Duc Duy Vo: BMC
Emma R. Scaletti: Stockholm University
Elisée Wiita: Karolinska Institute
Ingrid Almlöf: Karolinska Institute
Olov Wallner: Karolinska Institute
Jonathan Davies: Stockholm University
Sara Košenina: Stockholm University
Liuzhen Meng: Karolinska Institute
Maeve Long: Karolinska Institute
Oliver Mortusewicz: Karolinska Institute
Geoffrey Masuyer: Stockholm University
Flavio Ballante: BMC
Maurice Michel: Karolinska Institute
Evert Homan: Karolinska Institute
Martin Scobie: Karolinska Institute
Christina Kalderén: Karolinska Institute
Ulrika Warpman Berglund: Karolinska Institute
Andrii V. Tarnovskiy: Enamine Ltd.
Dmytro S. Radchenko: Enamine Ltd.
Yurii S. Moroz: Enamine Ltd.
Jan Kihlberg: Uppsala University
Pål Stenmark: Stockholm University
Thomas Helleday: Karolinska Institute
Jens Carlsson: BMC

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

Abstract: Abstract Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 1022 compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets.

Date: 2025
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DOI: 10.1038/s41467-025-56893-9

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