Discovery of new inhibitors of D-alanine:D-alanine ligase by structure-based virtual screening.
The terminal dipeptide, D-Ala-D-Ala, of the peptidoglycan precursor UDPMurNAc-pentapetide is a crucial building block involved in peptidoglycan cross-linking. It is synthesized in the bacterial cytoplasm by the enzyme d-alanine:d-alanine ligase (Ddl). Structure-based virtual screening of the NCI diversity set of almost 2000 compounds was performed with a DdlB isoform from Escherichia coli using the computational tool AutoDock 4.0. The 130 best-ranked compounds from this screen were tested in an in vitro assay for their inhibition of E. coli DdlB. Three compounds were identified that inhibit the enzyme with K(i) values in micromolar range. Two of these also have promising antibacterial activities against Gram-positive and Gram-negative bacteria.
Kovac
Andreja
A
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Konc
Janez
J
Vehar
Blaz
B
Bostock
Julieanne M
JM
Chopra
Ian
I
Janezic
Dusanka
D
Gobec
Stanislav
S
D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase