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NDDP
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)