8DDE

The N-terminal domain of PA endonuclease from the influenza H1N1 viral polymerase in complex with 4-(benzyloxy)-6-bromo-2-(1H-tetrazol-5-yl) yridine-3-ol

8DDE の概要

• エントリーDOI: 10.2210/pdb8dde/pdb
• 関連するPDBエントリー: 7V04 8CTF 8DAL 8DDB
• 分子名称: Polymerase acidic protein, (2M)-6-bromo-3-hydroxy-2-(1H-tetrazol-5-yl)pyridin-4(1H)-one, MANGANESE (II) ION, ... (4 entities in total)
• 機能のキーワード: drug discovery, metal-binding pharmacophore, isosteres, influenza endonuclease, viral protein-inhibitor complex, viral protein, hydrolase-inhibitor complex, 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: 22792.39

構造登録者

Kohlbrand, A.J.,Stokes, R.W.,Karges, J.,Seo, H.,Sankaran, B.,Cohen, S.M. (登録日: 2022-06-17, 公開日: 2022-12-21, 最終更新日: 2023-10-25)

主引用文献

Stokes, R.W.,Kohlbrand, A.J.,Seo, H.,Sankaran, B.,Karges, J.,Cohen, S.M.
Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors.
Acs Med.Chem.Lett., 14:75-82, 2023

PubMed Abstract: Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PA using a FRET-based enzymatic assay, and their mode of binding in PA was determined using X-ray crystallography.

PubMed: 36655124
DOI: 10.1021/acsmedchemlett.2c00434

実験手法

X-RAY DIFFRACTION (2.22 Å)