From hit to lead: De novo design based on virtual screening hits of inhibitors of tRNA-guanine transglycosylase, a putative target of shigellosis therapy

Shigellosis, a bacterial disease, causes the death of more than one million people per year. Extensive studies of Shigella flexneri have recognized tRNA-guanine transglycosylase (TGT, EC 2.4.2.29) as one of the key enzymes involved in the regulation of bacterial virulence. Based on the crystal structure of the Zymomonas mobilis enzyme, we have embarked on the rational design of TGT inhibitors. Herein, we describe the structure-based optimization of hits previously found by virtual screening (see Tables 1 - 3). For the pteridines, the most potent compound class discovered in a previous virtual screening run, a versatile synthesis could be established giving access to a broad range of substituted derivatives (see Scheme 5). The best ligand in this series, 14, exhibits a K-i = 0.45 muM.