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Solution-based indirect affinity selection mass spectrometry--a general tool for high-throughput screening of
Thomas N O'Connell1, Jason Ramsay, Steven F Rieth
1Center of Chemistry Innovation and Excellence and ‡Research Informatics, Pfizer, Inc. , Groton, Connecticut 06340, United States.
Analytical Chemistry
|July 18, 2014
Summary
An automated affinity selection mass spectrometry system was built using commercial parts for high-throughput compound screening. This method accelerates hit identification for drug discovery by simplifying analysis.
Area of Science:
- Biochemistry
- Analytical Chemistry
- Drug Discovery
Background:
- High-throughput screening (HTS) is crucial for identifying novel drug candidates.
- Traditional HTS methods can be time-consuming and require extensive development.
- Automated systems offer potential for increased efficiency in compound screening.
Purpose of the Study:
- To develop and demonstrate an automated solution-based affinity selection mass spectrometry (ASMS) system.
- To evaluate the system's performance in terms of throughput and hit identification.
- To showcase the system's applicability using a known biological target.
Main Methods:
- Construction of an automated ASMS system using only commercially available components.
- Utilizing a binding assay format for compound selection.
- Employing exact mass analysis for simplified hit identification.
- Testing the system with carbonic anhydrase as the target and a library of 144,000 compounds.
Main Results:
- Successful construction of a fully automated ASMS system.
- Achieved high throughput of approximately 1 × 10^5 compounds per day.
- Demonstrated a low hit rate, characteristic of affinity selection methods.
- Confirmed the system's ability to rapidly identify potential binders.
Conclusions:
- Automated ASMS is a feasible and efficient technology for drug discovery.
- The system offers a rapid timeline from target availability to hit identification.
- Commercial availability of components lowers the barrier to adopting this technology.
- Exact mass analysis enhances the reliability of hit identification in ASMS.
