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In this specific targeted research project we intend to use cutting-edge nuclear magnetic resonance (NMR) techniques to develop a fast, integrated approach to support structure-based drug design. The project will speed up drug design efforts for typical drug targets and will shorten the lead-time for new drugs. We will develop fast, reliable and robust NMR techniques for an exact structural and dynamic characterization of drug-receptor interactions at atomic resolution, thus enabling and/or improving the potential for the directed development of drugs exhibiting a maximum of desired interaction characteristics in a relatively short time. Protocols for obtaining the NMR parameters needed for the characterization of proteins, inhibitors and protein-inhibitor complexes will be developed, starting from known X-ray structures, thus establishing a tight connection between NMR and X-ray technology and exploiting optimally the complementary strengths of both techniques. The NMR technologies to be developed will be complemented by new, fast computer modelling approaches for protein-inhibitor complexes and by specific advanced tailored protein expression methods. In order to show the impact for drug development, the NMR protocols will be developed and tested using phosphatases, a major class of drug targets for a broad range of medical indications. The majority of cellular functions depend on phosphorylation by kinases and de-phosphorylation by phosphatases. High eukaryotes encode approximately 500 protein kinase and 100 protein phosphatase schemes, corresponding to 3% of their genome. While the importance of kinases in cellular regulation has lead to substantial drug design activities, the importance of phosphatases has only been appreciated recently. Protein phosphatases regulate insulin signaling, cell growth and the cell cycle. Therefore, the inhibition of phosphatases is perused for the treatment of diabetes and obesity and various types of cancer. The availability of the human genome provides access to a broad variety of phosphatases and allows systematic drug design using sophisticated techniques to identify potential inhibitors.

NDDP is a STREP Funded by the 6th Research Framework Program of the European Union
(Contract: LSHG-CT-2004-512077)