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Publication Abstract from PubMed

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 IC 50 values ranging from 80 to 600 muM. 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.

Novel Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme.,Humljan J, Kotnik M, Contreras-Martel C, Blanot D, Urleb U, Dessen A, Solmajer T, Gobec S J Med Chem. 2008 Nov 13. PMID:19007109^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.