2Y66

New 5-Benzylidenethiazolidine-4-one Inhibitors of Bacterial MurD Ligase: Design, Synthesis, Crystal Structures, and Biological Evaluation

Summary for 2Y66

• Entry DOI: 10.2210/pdb2y66/pdb
• Related: 1E0D 1EEH 1UAG 2JFF 2JFG 2JFH 2UAG 2UUO 2UUP 2VTD 2VTE 2WJP 2X5O 2Y1O 2Y67 2Y68 3UAG 4UAG
• Descriptor: UDP-N-ACETYLMURAMOYLALANINE--D-GLUTAMATE LIGASE, (2R)-2-[[3-[[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy]methyl]phenyl]carbonylamino]pentanedioic acid, DIMETHYL SULFOXIDE, ... (7 entities in total)
• Functional Keywords: atp-binding, cell cycle, cell division, cell shape, cell wall biogenesis/degradation, ligase, nucleotide-binding, peptidoglycan synthesis, uma
• Biological source: ESCHERICHIA COLI
• Cellular location: Cytoplasm: P14900
• Total number of polymer chains: 1
• Total formula weight: 48753.59

Authors

Zidar, N.,Tomasic, T.,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: 2011-10-19, Last modification date: 2023-12-20)

Primary citation

Zidar, N.,Tomasic, T.,Sink, R.,Kovac, A.,Patin, D.,Blanot, D.,Contreras-Martel, C.,Dessen, A.,Premru, M.M.,Zega, A.,Gobec, S.,Masic, L.P.,Kikelj, D.
New 5-Benzylidenethiazolidin-4-One Inhibitors of Bacterial Murd Ligase: Design, Synthesis, Crystal Structures, and Biological Evaluation.
Eur.J.Med.Chem, 46:5512-, 2011

PubMed Abstract: Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC(50) values up to 28 μM. Inhibitor 37, with an IC(50) of 34 μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.

PubMed: 21963114
DOI: 10.1016/J.EJMECH.2011.09.017

Experimental method

X-RAY DIFFRACTION (1.49 Å)