7OC7

LasB, alpha-alkyl-N-aryl mercaptoacetamide

7OC7 の概要

• エントリーDOI: 10.2210/pdb7oc7/pdb
• 分子名称: Neutral metalloproteinase, ZINC ION, (2R)-N,3-diphenyl-2-sulfanyl-propanamide, ... (5 entities in total)
• 機能のキーワード: lasb, alpha-alkyl-n-aryl mercaptoacetamide, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33422.16

構造登録者

Koehnke, J.,Sikandar, A. (登録日: 2021-04-26, 公開日: 2022-01-19, 最終更新日: 2024-11-13)

主引用文献

Kaya, C.,Walter, I.,Yahiaoui, S.,Sikandar, A.,Alhayek, A.,Konstantinovic, J.,Kany, A.M.,Haupenthal, J.,Kohnke, J.,Hartmann, R.W.,Hirsch, A.K.H.
Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors.
Angew.Chem.Int.Ed.Engl., 61:e202112295-e202112295, 2022

PubMed Abstract: Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.

PubMed: 34762767
DOI: 10.1002/anie.202112295

実験手法

X-RAY DIFFRACTION (1.95 Å)