Searching for conformationally‐selective small molecule therapeutics using ion mobility‐mass spectrometry (227.1)

Mass Spectrometry (MS) plays a number of key roles in the discovery and development phases for modern pharmaceutical compounds. Historically, however, MS has had a relatively limited role 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 through enzyme activities. This fact is driving the development of high‐throughput analytical tools that put a stronger emphasis on protein structure information. We have been actively developing nano‐electrospray ionization coupled to ion mobility‐mass spectrometry (IM‐MS) into such a tool. Our IM‐MS protocols include the collision induced unfolding (CIU) of proteins and complexes, which functions as a highly‐sensitive and selective analog of isothermal calorimetry for gas‐phase protein‐ligand complexes, able to characterize protein stabilities at low concentrations within mixtures. Here, we will present our latest results where we demonstrate the ability of this technology to detect activation state‐selective kinase inhibitors, evaluate key conformational changes within amyloid protein‐ligand complexes, and identify signatures associated with cooperative ligand binding within multiprotein assemblies.