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Abstract
In this STREP 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 exact structural and dynamic characterization of drug-receptor interactions at atomic resolution, thus enabling and / or improving the potential for directed development of drugs exhibiting a maximum of desired interaction characteristics in a relatively short time. Protocols for obtaining the NMR data 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 new NMR technologies will be complemented by computer modelling for protein-inhibitor complexes and by advanced tailored protein expression methods.
In order to show the impact for drug development, the new approach will aim at phosphatases, a major class of drug targets with broad medical implications. A majority of cellular functions depend on phosphorylation by kinases and de-phosphorylation by phosphatases. High eukaryotes encode approximately 500 kinase and 100 phosphatase schemes, corresponding to 3% of the genome. While the importance of kinases in cellular regulation led to substantial drug design activities, the importance of phosphatases has only been appreciated recently. Phosphatases regulate insulin signalling, cell growth and the cell cycle. Therefore, the inhibition of phosphatases is perused for the treatment of diabetes, obesity and various cancers. Human genome data provide access to a broad range of phosphatases, allowing systematic drug design using advanced 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)