High-affinity inhibitors of Zymomonas mobilis tRNA-guanine transglycosylase through convergent optimization.
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| 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.
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| Authors | Luzi Jakob Barandun, Florian Immekus, Philipp C Kohler, Tina Ritschel, Andreas Heine, Pierfrancesco Orlando, Gerhard Klebe, François Diederich |
| Journal | Acta crystallographica. Section D, Biological crystallography (Acta Crystallogr D Biol Crystallogr) Vol. 69 Issue Pt 9 Pg. 1798-807 (Sep 2013) ISSN: 1399-0047 [Electronic] United States |
| PMID | 23999303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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