title: Discovery of new inhibitors of D-alanine:D-alanine ligase by structure-based virtual screening.
abstract: 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.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovac
authors.forename: Janez
authors.initials: J
authors.lastname: Konc
authors.forename: Blaz
authors.initials: B
authors.lastname: Vehar
authors.forename: Julieanne M
authors.initials: JM
authors.lastname: Bostock
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
authors.forename: Dusanka
authors.initials: D
authors.lastname: Janezic
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase