Virtual screening for submicromolar leads of tRNA-guanine transglycosylase based on a new unexpected binding mode detected by crystal structure analysis.
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.
Brenk
Ruth
R
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
Naerum
Lars
L
Grädler
Ulrich
U
Gerber
Hans-Dieter
HD
Garcia
George A
GA
Reuter
Klaus
K
Stubbs
Milton T
MT
Klebe
Gerhard
G
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
D004791:Enzyme Inhibitors; D006834:Hydrazines; D008024:Ligands; D010880:Piperidines; D011622:Pterins; D011720:Pyrazoles; D011724:Pyridazines; D006147:Guanine; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase