6E4C

The N-terminal domain of PA endonuclease from the influenza H1N1 virus in complex with 3-hydroxy-6-(2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid

6E4C の概要

• エントリーDOI: 10.2210/pdb6e4c/pdb
• 関連するPDBエントリー: 6E3M 6E3N 6E3O 6E3P
• 分子名称: Polymerase acidic protein, MANGANESE (II) ION, 3-hydroxy-6-[2-methyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-4-oxo-1,4-dihydropyridine-2-carboxylic acid, ... (5 entities in total)
• 機能のキーワード: pa endonuclease, inhibitor, influenza, h1n1, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Influenza A virus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22969.87

構造登録者

Morrison, C.N.,Dick, B.L.,Credille, C.V.,Cohen, S.M. (登録日: 2018-07-17, 公開日: 2019-07-17, 最終更新日: 2023-10-11)

主引用文献

Credille, C.V.,Morrison, C.N.,Stokes, R.W.,Dick, B.L.,Feng, Y.,Sun, J.,Chen, Y.,Cohen, S.M.
SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease.
J.Med.Chem., 62:9438-9449, 2019

PubMed Abstract: Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PA) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PA endonuclease inhibition, a fragment-based drug development campaign was pursued. Guided by coordination chemistry and structure-based drug design, MBP scaffolds were elaborated to improve activity and selectivity. Structure-activity relationships were established and used to generate inhibitors of influenza endonuclease with tight-binding affinities. The activity of these inhibitors was analyzed using a fluorescence-quenching-based nuclease activity assay, and binding was validated using differential scanning fluorometry. Lead compounds were found to be highly selective for PA endonuclease against several related dinuclear and mononuclear metalloenzymes. Combining principles of bioinorganic and medicinal chemistry in this study has resulted in some of the most active in vitro influenza PA endonuclease inhibitors with high ligand efficiencies.

PubMed: 31536340
DOI: 10.1021/acs.jmedchem.9b00747

実験手法

X-RAY DIFFRACTION (2.35 Å)