2Y68

Structure-based design of a new series of D-glutamic acid-based inhibitors of bacterial MurD ligase

Summary for 2Y68

• Entry DOI: 10.2210/pdb2y68/pdb
• Related: 1E0D 1EEH 1UAG 2JFF 2JFG 2JFH 2UAG 2UUO 2UUP 2VTD 2VTE 2WJP 2X5O 2Y1O 2Y66 2Y67 3UAG 4UAG
• Descriptor: UDP-N-ACETYLMURAMOYLALANINE--D-GLUTAMATE LIGASE, 2-[[2-fluoro-5-[[[4-[(Z)-(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]phenyl]amino]methyl]phenyl]carbonylamino]pentanedioic acid, DIMETHYL SULFOXIDE, ... (7 entities in total)
• Functional Keywords: atp-binding, cell cycle, cell division, cell shape, cell wall, cell wall biogenesis/degradation, ligase, nucleotide-binding, peptidoglycan synthesis, uma
• Biological source: Escherichia coli K-12
• Cellular location: Cytoplasm: P14900
• Total number of polymer chains: 1
• Total formula weight: 49311.91

Authors

Tomasic, T.,Zidar, N.,Sink, R.,Kovac, A.,Patin, D.,Blanot, D.,Contreras-Martel, C.,Dessen, A.,Muller-Premru, M.,Zega, A.,Gobec, S.,Peterlin-Masic, L.,Kikelj, D. (deposition date: 2011-01-20, release date: 2011-06-08, Last modification date: 2023-12-20)

Primary citation

Tomasic, T.,Zidar, N.,Sink, R.,Kovac, A.,Blanot, D.,Contreras-Martel, C.,Dessen, A.,Muller-Premru, M.,Zega, A.,Gobec, S.,Kikelj, D.,Masic, L.P.
Structure-based design of a new series of D-glutamic acid based inhibitors of bacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD).
J. Med. Chem., 54:4600-4610, 2011

PubMed Abstract: MurD ligase is one of the key enzymes participating in the intracellular steps of peptidoglycan biosynthesis and constitutes a viable target in the search for novel antibacterial drugs to combat bacterial drug-resistance. We have designed, synthesized, and evaluated a new series of D-glutamic acid-based Escherichia coli MurD inhibitors incorporating the 5-benzylidenethiazolidin-4-one scaffold. The crystal structure of 16 in the MurD active site has provided a good starting point for the design of structurally optimized inhibitors 73-75 endowed with improved MurD inhibitory potency (IC(50) between 3 and 7 μM). Inhibitors 74 and 75 showed weak activity against Gram-positive Staphylococcus aureus and Enterococcus faecalis. Compounds 73-75, with IC(50) values in the low micromolar range, represent the most potent D-Glu-based MurD inhibitors reported to date.

PubMed: 21591605
DOI: 10.1021/jm2002525

Experimental method

X-RAY DIFFRACTION (1.49 Å)