title: Discovery of new MurA inhibitors using induced-fit simulation and docking.
abstract: We report on the successful application of ProBiS-CHARMMing web server in the discovery of new inhibitors of MurA, an enzyme that catalyzes the first committed cytoplasmic step of bacterial peptidoglycan synthesis. The available crystal structures of Escherichia coli MurA in the Protein Data Bank have binding sites whose small volume does not permit the docking of drug-like molecules. To prepare the binding site for docking, the ProBiS-CHARMMing web server was used to simulate the induced-fit effect upon ligand binding to MurA, resulting in a larger, more holo-like binding site. The docking of a filtered ZINC compound library to this enlarged binding site was then performed and resulted in three compounds with promising inhibitory potencies against MurA. Compound 1 displayed significant inhibitory potency with IC50value of 1μM. All three compounds have novel chemical structures, which could be used for further optimization of small-molecule MurA inhibitors.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Kaja
authors.initials: K
authors.lastname: Rožman
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Lešnik
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrast
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.affiliation: Group Bacterial Cell Envelopes and Antibiotics, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Patin
authors.affiliation: Group Bacterial Cell Envelopes and Antibiotics, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Barreteau
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Konc
authors.affiliation: Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia. Electronic address: dusanka.janezic@upr.si.
authors.forename: Dušanka
authors.initials: D
authors.lastname: Janežič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002240:Carbohydrate Sequence; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010457:Peptidoglycan / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase
keywords: Antibacterial agents; Induced fit; MurA inhibitors; ProBiS-CHARMMing web server; Small-molecule inhibitors