Structure-Based Drug Design

Prof. Dr. Gerhard Klebe, Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Germany

“The main focus of our work lies on structure based-drug design. In this context,we study the interaction of the bacterial tRNA modifying enzyme tRNA-guaninetransglycosylase (Tgt) with small molecule inhibitors and with tRNA. Althoughwe were unable to measure any interaction of this enzyme with its small moleculesubstrates guanine and 7-deaza-7-aminomethyl guanine via MST, a strong influenceon the thermophoretic behaviour of Tgt was noticed upon binding of the Macromolecular tRNA substrate allowing determination of the respective Kd value.In addition, MSTyielded Kd values for lin-benzoguanine-based Tgt inhibitors (300-500 Da), which wereexcellently consistent with Ki values previously determined in enzyme kinetic studies. Accordingly, this fast and easy to use method provides a highly welcome alternativeto the radioactive enzyme assay we used so far to figure out binding affinities of Tgtinhibitors. Furthermore, we investigate the interaction of a chaperone of the Shigellatype III secretion system with its protein interaction partners or rather with syntheticpeptides thereof to identify the respective recognition motifs. Via MST, we determinedwith low amounts of protein material Kd values which were in nearly perfect agreementwith those measured via isothermal titration calorimetry.”

Prof. Gerhard Klebe