Contact

Prof. Jörg Rademann

phone +49 30 9406 2981
fax +49 30 9406 2901
rademann(at)fmp-berlin.de

Medicinal Chemistry (Jörg Rademann )

Please note
Prof. Jörg Rademann has accepted the chair for Medicinal Chemistry at theUniversität Leipzig in April 2010, but he still has coworkers at the FMP.

You can reach Prof. Rademann in Leipzig:
Prof. Dr. Jörg Rademann
Brüderstraße 34
04103 Leipzig
Tel.: + 49 341 97 36 800/ 801
Fax: + 49 341 97 36 889
rademann(at)uni-leipzig.de

 

Introduction

(c) FMP 2008/2009

The group identifies and optimizes small molecules as specific biological effectors for studying protein structure, protein function and as potential starting points for pharmacological intervention. By doing so, the group enables the translation of biological knowledge gained in the areas of structure biology and cell biology into pharmacologically relevant small molecules.
For this purpose, we develop strategies in the areas of synthetic organic chemistry, library design, and bioassays. Most protein targets of the group are disease-related enzymes including proteases and phosphatases relevant to clinical indications including cancer, Alzheimer, tuberculosis, and SARS. Recently, the targeted proteins have been extended towards receptors and protein-protein interactions.

 

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.

Figure 2. Targeting protein-protein interactions with small molecule inhibitors.
Figure 2. Targeting protein-protein interactions with small molecule inhibitors.

Starting the ChemBioNet

For a strengthening of the FMP-activities in the area of chemical biology we have co-initiated the national collaboration network “ChemBioNet”. In collaboration with the GBF, Braunschweig, and the MDC, Berlin an open screening library has been composed and is available for screening by academic groups. Sublibraries of proprietary compounds synthesized by chemists from outside the FMP are deposited to make them accessible for screening. The library concept will be accompanied by a database to communicate the contents of libraries together with screening results to external users. In addition, the ChemBioNet has initiated a Fachsektion “Chemische Biologie” at the Dechema to support the development of chemical biology in Germany and Europe and I am representing the FMP on the elected board of this network as its vice president.

Literature:

J. Bauer, J. RademannHydrophobically assisted switching phase synthesis: The flexible combination of solid-phase and solution-phase reactions employed for oligosaccharide preparation” J. Am. Chem. Soc. 2005, 127, 7296-7297.
S. Weik, T. Luksch, A. Evers, J. Böttcher, A. Hasilik, H.-G. Löffler, G. Klebe, J. Rademann „The potential of P1 site alterations in peptidomimetic inhibitors explored via virtual screening and the use of CC-coupling linker reagents” ChemMedChem 2006, 1, 445-457.
S. I. Al-Gharabli, S. T. Ali Shah, S. Weik,, M. Schmidt, J. R. Mesters, D. Kuhn, G. Klebe, R. Hilgenfeld, J. Rademann An efficient method for the synthesis of peptide aldehyde libraries employed in the discovery of SARS coronavirus main protease (SARS-CoV Mpro) inhibitors” ChemBioChem 2006, 7,1048-1055.

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Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
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+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de