Chemical Biology with small molecules

In order to identify small molecules as powerful and specific biological switches, chemical libraries are designed and composed. For the synthesis of proprietary, focused libraries, we develop and apply methods of combinatorial chemistry conducted in solution, with polymer reagents, and on solid phase. Library syntheses in most cases are operated in parallel with medium throughput. Synthetic expertise in the group is mainly developed for major heterocyclic hit classes. Further strongholds are in the areas of peptidomimetics and carbohydrate derivatives.
In order to extend single fragment hits to extended higher affinity ligands we develop dynamic fragment ligation concepts. For targeting multivalent binding sites and proteins we have presented a concept for the preparation of multivalent ligands, that should enable us to investigate the multivalency of a binding site in biological systems as well as to increase the affinity of monovalent ligands significantly. The synthetic work in the group is supplemented by analytic expertise including LC-MS and NMR facility.

 

Bioassays and library design

The medicinal chemistry group supports the assay development by synthesizing fluorophore-labelled substrates and the set-up mostly of fluorescence polarization-based detection. For library design we apply a fragment-based concept. From the algorithmic analysis of a bioactive compound data bank, common substructure elements have been derived and are used systematically for library composition. By this approach we can guarantee optimal hit rates with comparably limited library size. Simultaneously, we can assure that the obtained hits are useful starting points for subsequent chemical ligand optimization. Hits derived from the high-throughput screening are evaluated by a medicinal chemistry panel that including scientists from the screening unit and the molecular modelling group.

 

Targeting protein-protein interactions

The group has initiated a program for the inhibition of protein-protein interactions which are commonly considered as “difficult” targets for pharmacological intervention but which are crucial for understanding and manipulating signalling networks in cells. As several groups at the FMP are interest vividly in protein-protein interaction this initiative is essential for crosslinking and complementing the research activities at the FMP. To achieve this goal we have established methodology for the set-up of bioassays based on the reduction of protein-protein interactions to peptide protein interactions. We can generate libraries of fluorophore-labelled molecules that serve as probes in fluorescent polarization assays in order to identify competitive small molecule binders.
The same fluorophore-labelled ligands can be used in cellular assays to localize binding partners. Moreover, the immobilization of the identified ligand on beads will be used for the affinity-based fishing of those proteins interacting with the small molecule ligand directly from cell lysates. Fished proteins will be identified in collaboration with the mass spectrometry group.