7ORZ

Crystal structure of UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) from Pseudomonas aeruginosa in complex with FAD and a pyrazole derivative (fragment 18)

7ORZ の概要

• エントリーDOI: 10.2210/pdb7orz/pdb
• 関連するPDBエントリー: 7OR2
• 分子名称: UDP-N-acetylenolpyruvoylglucosamine reductase, 1-phenyl-5-(trifluoromethyl)pyrazole-4-carboxylic acid, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: peptidoglycan-biosynthesis, fragment based drug discovery, oxidoreductase
• 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: 38594.41

構造登録者

Acebron-Garcia de Eulate, M.,Blundell, T.L.,Kim, S.Y.,Mendes, V.,Abell, C. (登録日: 2021-06-06, 公開日: 2021-11-03, 最終更新日: 2024-01-31)

主引用文献

Acebron-Garcia-de-Eulate, M.,Mayol-Llinas, J.,Holland, M.T.O.,Kim, S.Y.,Brown, K.P.,Marchetti, C.,Hess, J.,Di Pietro, O.,Mendes, V.,Abell, C.,Floto, R.A.,Coyne, A.G.,Blundell, T.L.
Discovery of Novel Inhibitors of Uridine Diphosphate- N -Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa , an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients.
J.Med.Chem., 65:2149-2173, 2022

PubMed Abstract: is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against . MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in , and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with = 3.57 μM (LE 0.35).

PubMed: 35080396
DOI: 10.1021/acs.jmedchem.1c01684

実験手法

X-RAY DIFFRACTION (1.85 Å)