Shigellosis, caused by the Shigella bacterium, is an intestinal infection. The emergence of multidrug-resistant strains demands the development of novel drugs. tRNA-guanine transglycosylase (TGT), one enzyme involved in the virulence mechanism, has been identified as a drug target and inhibition was shown to reduce virulence dramatically. Due to the structural similarity of the active sites, the Z. mobilisTGT has been utilized as a model system.A lin-benzoguanine scaffold was previously identified as the central core of a series of highly potent inhibitors.1 The high affinity can be explained by a charge-assisted hydrogen bond, which could recently be investigated in more detail by isothermal titration calorimetry (ITC).2 Comparison of a series of lin-benzoguanines and lin-benzohypoxanthines reveals significant changes in the binding mode, inhibition constant, and pKa values. The binding modes were resolved by several X-ray crystal structures of TGT�ligand complexes.31 S. R. H�rtner, T. Ritschel, B. Stengl, C. Kramer, W. B. Schweizer, B. Wagner, M. Kansy, G. Klebe, F. Diederich, Angew. Chem. 2007  , 119, 8414�8417; Angew. Chem. Int. Ed. 2007  , 46, 8266�8269.2 M. Neeb, P. Czodrowski, A. Heine, L. Barandun, C. Hohn, F. Diederich, G. Klebe, submitted to J. Med. Chem.3 L. J. Barandun, F. Immekus. P. C. Kohler, S. Tonazzi, B. Wagner, S. Wendelspiess, T. Ritschel, A. Heine, M. Kansy, G. Klebe, F. Diederich, Chem. Eur. J. 2012  , 18, 9246�9257.

Potent inhibition of <i>t</i>RNA-guanine transglycosylase investigated by isothermal titration calorimetry

248th National Meeting (2014)

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Potent inhibition of tRNA-guanine transglycosylase investigated by isothermal titration calorimetry