title: High-affinity inhibitors of Zymomonas mobilis tRNA-guanine transglycosylase through convergent optimization.
abstract: The tRNA-modifying enzyme tRNA-guanine transglycosylase (TGT) has been recognized as a drug target for the treatment of the foodborne illness shigellosis. The active site of TGT consists of three pockets: the central guanine/preQ1 recognition site and the ribose-33 and ribose-34 pockets. In previous work, lin-benzoguanines and lin-benzohypoxanthines, which differ by the presence of an exocyclic NH2 group in the former and its absence in the latter, were used as central scaffolds that bind to the guanine/preQ1 recognition site and allow suitable functionalization along exit vectors targeting the two ribose pockets. The substituents for both of these two pockets have been optimized individually. Here, a series of bifunctionalized inhibitors that occupy both ribose pockets are reported for the first time. Dissociation constants Kd down to the picomolar range were measured for the bifunctionalized lin-benzoguanine-based ligands and Kd values in the nanomolar range were measured for the corresponding lin-benzohypoxanthine-based ligands. The binding mode of all inhibitors was elucidated by X-ray crystal structure analysis. A remarkable influence of the crystallization protocol on the solvation pattern in the solid state and the residual mobility of the bound ligands was observed.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zurich, Switzerland.
authors.forename: Luzi Jakob
authors.initials: LJ
authors.lastname: Barandun
authors.forename: Florian
authors.initials: F
authors.lastname: Immekus
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Kohler
authors.forename: Tina
authors.initials: T
authors.lastname: Ritschel
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Orlando
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D006147:Guanine / Q000031:analogs & derivatives; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017355:Zymomonas / Q000201:enzymology*
chemical_list: D006147:Guanine; C019549:queuine; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase
keywords: Zymomonas mobilis; lin-benzopurine inhibitors; shigellosis; tRNA–guanine transglycosylase