The ability to localize the physical interactions of proteins with candidate small molecule ligands plays a central role in current small molecule drug discovery efforts. Until recently, only X-ray crystallography and NMR could provide the submolecular details of such interactions. Unfortunately, both techniques have applicability limitations: NMR is applicable only for relatively small proteins at relatively high concentration and not all protein-ligand interactions can be co-crystallized. The hydrogen exchange perturbation of a target protein upon ligand binding can be measured with DXMS as long as over 90% of the protein is in ligand-bound form in solution. No crystallization is necessary and micromolar binding affinities for ligand are sufficient for study. As for sensitivity, a few nano-moles of a protein is usually enough to complete the analysis, and recent developments have decreased protein requirements 100-fold or more .
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