Theoretical analysis of the competition ligand-based NMR experiments and selected applications to fragment screening and binding constant measurements

Competition ligand-based NMR experiments have recently emerged as a powerful approach for fragment-based screening in the drug discovery process. The robustness and reliability of these methodologies result in the identification of only specific binding ligands. In addition, the experiments, when properly performed, provide a quantitative measure of the affinity of the identified hits for the receptor. This is relevant for ranking the molecules according to their binding strength to the biomolecular target and for building a meaningful structure activity relationship (SAR) table. Several NMR experiments have been proposed for this purpose. The theory at the base of these different competition ligand-based NMR experiments is analyzed in detail and several simulations with experimental conditions typically used in the NMR screening experiments are reported. Most of the presented theory applies also to the direct ligand-based NMR screening experiments. In addition, the strategy for deriving the binding constant of the molecules is described, and selected applications to relevant drug discovery projects are presented. Finally, a novel sensitive NMR screening experiment that combines WaterLOGSY and transverse relaxation effects is proposed. (C) 2008 Wiley Periodicals, Inc.