7NBW

Crystal structure of PqsR (MvfR) ligand-binding domain in complex with a pyridin agonist

7NBW の概要

• エントリーDOI: 10.2210/pdb7nbw/pdb
• 分子名称: Transcriptional regulator MvfR, ~{N}-[3-(4-fluorophenyl)prop-2-ynyl]-2-(trifluoromethyl)pyridin-4-amine (3 entities in total)
• 機能のキーワード: quorum sensing, lysr-type transcriptional regulator, pseudomonas, 2 quinolone signaling system, lttr, dna binding protein
• 由来する生物種: Pseudomonas aeruginosa PAO1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25994.31

構造登録者

Schmelz, S.,Blankenfeldt, W. (登録日: 2021-01-28, 公開日: 2021-10-06, 最終更新日: 2024-01-31)

主引用文献

Schutz, C.,Hodzic, A.,Hamed, M.,Abdelsamie, A.S.,Kany, A.M.,Bauer, M.,Rohrig, T.,Schmelz, S.,Scrima, A.,Blankenfeldt, W.,Empting, M.
Divergent synthesis and biological evaluation of 2-(trifluoromethyl)pyridines as virulence-attenuating inverse agonists targeting PqsR.
Eur.J.Med.Chem., 226:113797-113797, 2021

PubMed Abstract: A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.

PubMed: 34520957
DOI: 10.1016/j.ejmech.2021.113797

実験手法

X-RAY DIFFRACTION (2.28 Å)