Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme.
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.
Humljan
Jan
J
Drug Discovery, Lek Pharmaceuticals d.d., Verovskova 57, 1526 Ljubljana, Slovenia.
Kotnik
Miha
M
Contreras-Martel
Carlos
C
Blanot
Didier
D
Urleb
Uros
U
Dessen
Andréa
A
Solmajer
Tom
T
Gobec
Stanislav
S
D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D010457:Peptidoglycan / Q000096:biosynthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009281:Naphthalenes; D010457:Peptidoglycan; C031721:naphthalene; D018698:Glutamic Acid; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase