4G2F

Human EphA3 kinase domain in complex with compound 7

4G2F の概要

• エントリーDOI: 10.2210/pdb4g2f/pdb
• 分子名称: EPH receptor A3, 1-amino-5-(5-hydroxy-2-methylphenyl)-7,8,9,10-tetrahydropyrimido[4,5-c]isoquinolin-6(5H)-one (3 entities in total)
• 機能のキーワード: receptor tyrosine kinase, atp binding, phosphorylation, membrane, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40780.54

構造登録者

Dong, J.,Caflisch, A. (登録日: 2012-07-12, 公開日: 2012-10-24, 最終更新日: 2023-11-08)

主引用文献

Zhao, H.,Dong, J.,Lafleur, K.,Nevado, C.,Caflisch, A.
Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics.
ACS MED.CHEM.LETT., 3:834-838, 2012

PubMed Abstract: We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 μM to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 Å resolution.

PubMed: 24900387
DOI: 10.1021/ml3001984

実験手法

X-RAY DIFFRACTION (1.699 Å)