Native electrospray ionization mass spectrometry has become an important method for the discovery and validation of noncovalent ligands for therapeutic targets. As a label-free method combining high sensitivity and chemical specificity, it is ideally suited for this application. However, the performance of the method is severely impacted by the presence of nonvolatile buffers and salts, and there is a risk of ion suppression if a target protein is coincubated with multiple candidate ligands. These factors, along with the fairly labor-intensive nature, required operator skill, and limited throughput of most implementations, represent significant obstacles to the widespread adoption of native mass spectrometry-based ligand discovery. Here, we demonstrate the combination of flow-induced dispersion analysis with native mass spectrometry for screening of ligands for an E3 ligase and two kinases of pharmacological relevance. Importantly, this approach avoids ion suppression and formation of salt adducts without the need for offline desalting or buffer exchange, and each multiplexed measurement of a sample consisting of a target protein and a mixture of more than 20 candidate ligands took only a few minutes. Because the method is largely automated, this screening technology represents a potentially important step toward making native mass spectrometry a mainstream biophysical technique in drug discovery.

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