title: Discovery of new inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurF by structure-based virtual screening.
abstract: The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys, and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute 'Diversity Set' on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC(50)=10 microM) and one novel MurF inhibitor (IC(50)=63 microM).
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovac
authors.forename: Audrey
authors.initials: A
authors.lastname: Boniface
authors.forename: Julieanne M
authors.initials: JM
authors.lastname: Bostock
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D019295:Computational Biology; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010457:Peptidoglycan / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D010453:Peptide Synthases; C060628:UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase