Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme

J Med Chem. 2008 Dec 11;51(23):7486-94. doi: 10.1021/jm800762u.


Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships.The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transition state analogues, displayed IC50 values ranging from 80 to 600 microM. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Naphthalenes / chemistry*
  • Peptide Synthases / antagonists & inhibitors*
  • Peptidoglycan / biosynthesis*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Naphthalenes
  • Peptidoglycan
  • naphthalene
  • Glutamic Acid
  • Peptide Synthases
  • UDP-N-acetylmuramoylalanine-D-glutamate ligase

Associated data

  • PDB/2UUO
  • PDB/2UUP
  • PDB/2VTD
  • PDB/2VTE