Development and application of a customized online affinity selection mass spectrometry screening platform.

Area of Science:

• Drug Discovery and Development
• Analytical Chemistry
• Biochemistry

Background:

• Affinity selection mass spectrometry (ASMS) is a key high-throughput screening method for drug discovery.
• Increasing chemical space and targeting historically undruggable targets necessitate ASMS platform improvements in efficiency and scalability.

Purpose of the Study:

• To develop and validate a customized online ASMS platform for enhanced drug screening.
• To improve the speed, efficiency, and data quality of ASMS workflows.

Main Methods:

• Implementation of multiplexed two-dimensional LC/MS for sample analysis.
• Integration of ultrafast acoustic ejection mass spectrometry for reaction product scouting.
• Development of an integrated tool for real-time data processing and cross-hit evaluation.

Main Results:

• The multiplexed ASMS platform demonstrated significantly enhanced analytical speed, efficiency, and capacity.
• The integrated data processing tool improved data quality by reducing false positives through advanced cross-hit assessments.
• The platform effectively streamlined the screening workflow by eliminating traditional bottlenecks.

Conclusions:

• The established online ASMS platform provides a robust solution for high-throughput screening.
• The system enables direct affinity ranking of hits from nanoscale synthesis, facilitating hit optimization and chemotype expansion.
• The platform demonstrates high performance for internal screening campaigns, generating tractable binding hits.