7OR2

Crystal structure of UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) from Pseudomonas aeruginosa in complex with FAD and a pyrazole derivative (fragment 4)

Summary for 7OR2

• Entry DOI: 10.2210/pdb7or2/pdb
• Descriptor: UDP-N-acetylenolpyruvoylglucosamine reductase, FLAVIN-ADENINE DINUCLEOTIDE, 5-methyl-1-phenyl-pyrazole-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: peptidoglycan-biosynthesis fragment based drug discovery, oxidoreductase
• Biological source: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• Total number of polymer chains: 1
• Total formula weight: 38753.70

Authors

Acebron-Garcia de Eulate, M.,Blundell, T.L.,Kim, S.Y.,Mendes, V.,Abell, C. (deposition date: 2021-06-04, release date: 2021-11-03, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)