Impact of Mass Spectrometry-Based Technologies and Strategies on Chemoproteomics as a Tool for Drug Discovery.

Chemoproteomics is an invaluable tool to discover protein targets from phenotypic assays and to understand on- and off-target engagement of potential therapeutic compounds. Highlighted in this technology perspective is our view on how improvements in mass spectrometry (MS)-based proteomics technology have dramatically impacted chemoproteomics. Improvements in sample preparation, MS instrumentation, data acquisition, and quantification strategies have enabled medicinal chemists, chemical biologists, and mass spectrometrists to develop new chemoproteomic experiments and improve existing methods. As a result of improvements in MS, we will detail how bead-based affinity capture and activity-based proteome profiling methods have been reduced from multiple LC-MS runs for samples and controls down to a single LC-MS run each for sample and control. With improvements in scan duty cycle and sensitivity, sufficient depth of proteome coverage can be obtained for capture-free methods, which do not utilize an enrichment step.