High-Throughput Mass Spectrometry for Hit Identification: Current Landscape and Future Perspectives

For nearly two decades mass spectrometry has been used as a label-free, direct-detection method for both functional and affinity-based screening of a wide range of therapeutically relevant target classes. Here, we present an overview of several established and emerging mass spectrometry platforms and summarize the unique strengths and performance characteristics of each as they apply to high-throughput screening. Multiple examples from the recent literature are highlighted in order to illustrate the power of each individual technique, with special emphasis given to cases where the use of mass spectrometry was found to be differentiating when compared with other detection formats. Indeed, as many of these examples will demonstrate, the inherent strengths of mass spectrometry-sensitivity, specificity, wide dynamic range, and amenability to complex matrices-can be leveraged to enhance the discriminating power and physiological relevance of assays included in screening cascades. It is our hope that this review will serve as a useful guide to readers of all backgrounds and experience levels on the applicability and benefits of mass spectrometry in the search for hits, leads, and, ultimately, drugs.

Automated summary

Mass spectrometry has been widely used as a label-free, direct-detection method for various therapeutically relevant target classes for nearly two decades. Different mass spectrometry platforms offer unique strengths and performance characteristics when it comes to high-throughput screening, with sensitivity, specificity, wide dynamic range, and adaptability to complex matrices being key advantages. By leveraging these inherent strengths, mass spectrometry can enhance the discriminating power and physiological relevance of assays in screening cascades for the search of hits, leads, and drugs.