Design und Synthese von Liganden für das Lektin FimH
Within this thesis a de novo drug design algorithm was applied, which includes the effects of explict water during the entire modelling process. The target protein – the lectin FimH – was subjected to molecular dynamics (md) simulations in aqueous mixtures of different pharmacophoric probe molecules. This setup allows to use DeltaG as determing energy function for the drug design process. From the resulting md trajectories 3-dimensional density distributions for the functional groups of the probe molecules (e. g. methanol, methylamine, benzene, cyclohexane) were calculated. Connecting several probes to a target molecule generated two lead structures. These molecules were synthesized to intermediat compounds which were tested for biological activity. Docking studies on several mannosides suggested modifications wich improved the ligand affinity. In addition, the structural behavior of glycocluster compound was investigated using md simulations.