5NGR

Crystal structure of human MTH1 in complex with fragment inhibitor 8-(methylsulfanyl)-7H-purin-6-amine

5NGR の概要

• エントリーDOI: 10.2210/pdb5ngr/pdb
• 関連するPDBエントリー: 5NGS 5NGT
• 分子名称: 7,8-dihydro-8-oxoguanine triphosphatase, 8-methylsulfanyl-7~{H}-purin-6-amine, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, fragment, oxidised nucleotides, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform p18: Cytoplasm. Isoform p26: Cytoplasm: P36639
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37446.29

構造登録者

Gustafsson, R.,Rudling, A.,Almlof, I.,Homan, E.,Scobie, M.,Warpman Berglund, U.,Helleday, T.,Carlsson, J.,Stenmark, P. (登録日: 2017-03-20, 公開日: 2017-10-04, 最終更新日: 2024-01-17)

主引用文献

Rudling, A.,Gustafsson, R.,Almlof, I.,Homan, E.,Scobie, M.,Warpman Berglund, U.,Helleday, T.,Stenmark, P.,Carlsson, J.
Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space.
J. Med. Chem., 60:8160-8169, 2017

PubMed Abstract: Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.

PubMed: 28929756
DOI: 10.1021/acs.jmedchem.7b01006

実験手法

X-RAY DIFFRACTION (2.2 Å)