title: Virtual screening for submicromolar leads of tRNA-guanine transglycosylase based on a new unexpected binding mode detected by crystal structure analysis.
abstract: Eubacterial tRNA-guanine transglycosylase (TGT) is involved in the hypermodification of cognate tRNAs, leading to the exchange of G34 by preQ1 at the wobble position in the anticodon loop. Mutation of the tgt gene in Shigella flexneri results in a significant loss of pathogenicity of the bacterium due to inefficient translation of a virulence protein mRNA. Herein, we describe the discovery of a ligand with an unexpected binding mode. On the basis of this binding mode, three slightly deviating pharmacophore hypotheses have been derived. Virtual screening based on this composite pharmacophore model retrieved a set of potential TGT inhibitors belonging to several compound classes. All nine tested inhibitors being representatives of these classes showed activity in the micromolar range, two of them even in the submicromolar range.
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Lars
authors.initials: L
authors.lastname: Naerum
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Gerber
authors.forename: George A
authors.initials: GA
authors.lastname: Garcia
authors.forename: Klaus
authors.initials: K
authors.lastname: Reuter
authors.forename: Milton T
authors.initials: MT
authors.lastname: Stubbs
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D011622:Pterins / Q000138:chemical synthesis / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D017355:Zymomonas / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D006834:Hydrazines; D008024:Ligands; D010880:Piperidines; D011622:Pterins; D011720:Pyrazoles; D011724:Pyridazines; D006147:Guanine; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase