Development and application of a customized online affinity selection mass spectrometry screening platform
With the evolving landscape of small molecule modalities and drug target portfolios, affinity selection mass spectrometry (ASMS) has emerged as a preferred high-throughput screening approach, driven by the growing chemical space capable of regulating historically undruggable targets. To meet the eve...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-08-01
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| Series: | SLAS Technology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2472630325000871 |
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| Summary: | With the evolving landscape of small molecule modalities and drug target portfolios, affinity selection mass spectrometry (ASMS) has emerged as a preferred high-throughput screening approach, driven by the growing chemical space capable of regulating historically undruggable targets. To meet the ever-increasing demand for binding screens, the ASMS platform requires continuous enhancements in efficiency and scalability. In this study, we developed a customized online ASMS platform, featuring multiplexed two-dimensional LC/MS for sample analysis, ultrafast acoustic ejection mass spectrometry for reaction product scouting of high-throughput chemistry before subjecting them to direct ASMS screens, and an integrated tool for real-time data processing and cross-hit evaluation. With the quality controls we implemented to ensure operational robustness and quality, the multiplexed system has demonstrated significantly enhanced analytical speed, efficiency, and overall capacity. The integrated data processing tool enhanced data quality by incorporating advanced cross-hit assessments to reduce false positives, and streamlined the screening workflow through real-time data analysis, effectively eliminating the traditional bottleneck in ASMS screening. The established ASMS platform has been utilized for our internal screening campaigns generating tractable binding hits, and providing direct affinity ranking of hits from nanoscale synthesis, enabling hit optimization and chemotype expansion with demonstrated high platform performance. |
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| ISSN: | 2472-6303 |