Nmr Screening By Waterlogsy Method

Water is known to play a key role in ligand-protein binding, with multiple water molecules being frequently observed at the ligand-protein interface, e.g. a layer of water was detected at the lovastatin/LFA-1 interface [49]. The intermolecular water-ligand NOEs are negative, indicating a residence time of >1 ns. Saturation of water results in magnetisation transfer from bulk water to bound water located in protein cavities and in the magnetisation transfer from bulk water to the layer of water at the protein-ligand interface. The group at Pharmacia developed an NMR technique called Water-Ligand observation with gradient spectroscopy (WaterLOGSY), which is able to detect binding of ligands to proteins via the magnetisation transfer from bulk water. The method was exemplified by the selection of an indole derivative from a mixture of 10 diverse compounds, which was found to bind to cyclin-dependent kinase 2 (cdk2). The compound (Figure 1.10) is reported to have a K in the high micromolar range [40].

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