Journal Article

Virtual fragment screening for DNA repair inhibitors in vast chemical space

Almlöf, Ingrid, Carlsson, Jens, Long, Maeve, Michel, Maurice, Scaletti, Emma R., Homan, Evert, Tarnovskiy, Andrii V., Vo, Duc Duy, Helleday, Thomas, Masuyer, Geoffrey, Ballante, Flavio, Wallner, Olov, Scobie, Martin, Moroz, Yurii S., Meng, Liuzhen, Wiita, Elisée, Davies, Jonathan, Košenina, Sara, Luttens, Andreas, Kalderén, Christina, Warpman Berglund, Ulrika, Radchenko, Dmytro S., Kihlberg, Jan, Mortusewicz, Oliver, Stenmark, Pål

2025

Overview

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 10 22 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. Fragment-based drug design is an efficient yet challenging approach for developing therapeutics. Here, the authors employ structure-based docking screens of vast fragment libraries to identify inhibitors of 8-oxoguanine DNA glycosylase, a difficult drug target implicated in cancer and inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 119/118 / 631/114/2248 / 631/154/309/2420 / 631/154/309/630 / 631/45/607/1159 / 631/535/1266 / 8-Hydroxyguanine / 82/47 / 82/80 / 82/83 / 96/98 / Cancer / Chemical compounds / Chemical synthesis / Combinatorial analysis / Combinatorial libraries / Crystallography / Crystallography, X-Ray / Deoxyribonucleic acid / DNA / DNA glycosylase / DNA Glycosylases - antagonists & inhibitors / DNA Glycosylases - chemistry / DNA Glycosylases - metabolism / DNA repair / DNA Repair - drug effects / DNA structure / Drug development / Drug discovery / Drug Discovery - methods / Drug Evaluation, Preclinical - methods / Enumeration / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Humanities and Social Sciences / Humans / Inflammation / Inhibitors / Molecular Docking Simulation / multidisciplinary / OGG1 protein / Pharmacology / Science / Science (multidisciplinary) / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Therapeutic targets / X-ray crystallography