8CEX

Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH11227.

8CEX の概要

• エントリーDOI: 10.2210/pdb8cex/pdb
• 分子名称: N-glycosylase/DNA lyase, 6-fluoranyl-N-[(4-methylphenyl)methyl]pyridine-3-carboxamide, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: protein in complex with fragment inhibitor, dna binding protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 107752.91

構造登録者

Kosenina, S.,Scaletti, E.R.,Stenmark, P. (登録日: 2023-02-02, 公開日: 2024-02-21, 最終更新日: 2025-03-12)

主引用文献

Luttens, A.,Vo, D.D.,Scaletti, E.R.,Wiita, E.,Almlof, I.,Wallner, O.,Davies, J.,Kosenina, S.,Meng, L.,Long, M.,Mortusewicz, O.,Masuyer, G.,Ballante, F.,Michel, M.,Homan, E.,Scobie, M.,Kalderen, C.,Warpman Berglund, U.,Tarnovskiy, A.V.,Radchenko, D.S.,Moroz, Y.S.,Kihlberg, J.,Stenmark, P.,Helleday, T.,Carlsson, J.
Virtual fragment screening for DNA repair inhibitors in vast chemical space.
Nat Commun, 16:1741-1741, 2025

PubMed 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 10 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.

PubMed: 39966348
DOI: 10.1038/s41467-025-56893-9

実験手法

X-RAY DIFFRACTION (2.3 Å)