2XPC

Second-generation sulfonamide inhibitors of MurD: Activity optimisation with conformationally rigid analogues of D-glutamic acid

Summary for 2XPC

• Entry DOI: 10.2210/pdb2xpc/pdb
• Descriptor: UDP-N-ACETYLMURAMOYLALANINE--D-GLUTAMATE LIGASE, (1R,3R,4S)-4-[({6-[(4-CYANO-2-FLUOROBENZYL)OXY]NAPHTHALEN-2-YL}SULFONYL)AMINO]CYCLOHEXANE-1,3-DICARBOXYLIC ACID, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: ligase, cell cycle, cell division, cell shape, cell wall biogenesis/degradation, ligase synthesis
• Biological source: ESCHERICHIA COLI
• Cellular location: Cytoplasm : Q8X9Y9
• Total number of polymer chains: 1
• Total formula weight: 48338.12

Authors

Sosic, I.,Barreteau, H.,Simcic, M.,Sink, R.,Cesar, J.,Golic-Grdadolnik, S.,Contreras-Martel, C.,Dessen, A.,Amoroso, A.,Joris, B.,Blanot, D.,Gobec, S. (deposition date: 2010-08-26, release date: 2011-05-18, Last modification date: 2023-12-20)

Primary citation

Sosi, I.,Barreteau, H.,Sim, M.,Sink, R.,Cesar, J.,Zega, A.,Grdadolnik, S.G.,Contreras-Martel, C.,Dessen, A.,Amoroso, A.,Joris, B.,Blanot, D.,Gobec, S.
Second-Generation Sulfonamide Inhibitors of D- Glutamic Acid-Adding Enzyme: Activity Optimisation with Conformationally Rigid Analogues of D- Glutamic Acid.
Eur.J.Med.Chem, 46:2880-, 2011

PubMed Abstract: D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities.

PubMed: 21524830
DOI: 10.1016/J.EJMECH.2011.04.011

Experimental method

X-RAY DIFFRACTION (1.49 Å)