5MMO

E. coli DNA Gyrase B 24 kDa ATPase domain in complex with [3-(3-ethyl-ureido)-5-(pyridin-4-yl)-isoquinolin-8-yl-methyl]-carbamic acid prop-2-ynyl ester

5MMO の概要

• エントリーDOI: 10.2210/pdb5mmo/pdb
• 分子名称: DNA gyrase subunit B, prop-2-ynyl ~{N}-[[3-(ethylcarbamoylamino)-5-pyridin-4-yl-isoquinolin-8-yl]methyl]carbamate, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, 009, isomerase
• 由来する生物種: Escherichia coli O157:H7
• 細胞内の位置: Cytoplasm : P0AES7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26374.44

構造登録者

Panchaud, P.,Bruyere, T.,Blumstein, A.-C.,Bur, D.,Chambovey, A.,Ertel, E.A.,Gude, M.,Hubschwerlen, C.,Jacob, L.,Kimmerlin, T.,Pfeifer, T.,Prade, L.,Seiler, P.,Ritz, D.,Rueedi, G. (登録日: 2016-12-12, 公開日: 2017-04-26, 最終更新日: 2024-05-08)

主引用文献

Panchaud, P.,Bruyere, T.,Blumstein, A.C.,Bur, D.,Chambovey, A.,Ertel, E.A.,Gude, M.,Hubschwerlen, C.,Jacob, L.,Kimmerlin, T.,Pfeifer, T.,Prade, L.,Seiler, P.,Ritz, D.,Rueedi, G.
Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.
J. Med. Chem., 60:3755-3775, 2017

PubMed Abstract: Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

PubMed: 28406299
DOI: 10.1021/acs.jmedchem.6b01834

実験手法

X-RAY DIFFRACTION (1.81 Å)