Ion mobility-mass spectrometry of intact protein--ligand complexes for pharmaceutical drug discovery and development

Abstract

Mass spectrometry (MS) plays a number of key roles in the discovery and development phases for modern pharmaceutical compounds, ranging from the assessment of protein-ligand binding to biomarker discovery. Historically, however, MS has had a relatively limited role in the drug discovery process in comparison to high-throughput fluorescence and radiometric screens. This picture may be changing, however, as many presumptive protein targets are coupled to human disease pathways through specific protein-protein interactions and protein conformations, rather than enzyme activities. This fact will likely drive the development of high-throughput analytical tools that put a stronger emphasis on the structural information content produced in a screen. Here we summarize recent developments surrounding ion mobility-mass spectrometry (IM-MS), one such MS-based tool that is capable of rapidly measuring changes in protein structure, oligomeric state, and binding stoichiometry from complex mixtures at relatively low concentrations.