6DCY

The N-terminal domain of PA endonuclease from the influenza H1N1 virus in complex with 5-hydroxy-2-methyl-4-oxo-4H-pyran-3-carboxylic acid

6DCY の概要

• エントリーDOI: 10.2210/pdb6dcy/pdb
• 分子名称: Polymerase acidic protein, MANGANESE (II) ION, 5-hydroxy-2-methyl-4-oxo-4H-pyran-3-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: inhibitor, endonuclease, influenza, pa domain, 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: 22748.66

構造登録者

Dick, B.L.,Morrison, C.N.,Cohen, S.M. (登録日: 2018-05-08, 公開日: 2018-11-07, 最終更新日: 2023-10-11)

主引用文献

Credille, C.V.,Dick, B.L.,Morrison, C.N.,Stokes, R.W.,Adamek, R.N.,Wu, N.C.,Wilson, I.A.,Cohen, S.M.
Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.
J. Med. Chem., 61:10206-10217, 2018

PubMed Abstract: Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PA endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PA endonuclease, a class of highly active and selective fragments was developed that displays IC values <50 nM. This SAR led to structurally distinct molecules that also displayed IC values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.

PubMed: 30351002
DOI: 10.1021/acs.jmedchem.8b01363

実験手法

X-RAY DIFFRACTION (2.08 Å)