Automatic mass spectrometry method development for drug discovery: application in metabolic stability assays

Area of Science:

• Pharmacology and Drug Discovery
• Analytical Chemistry
• Biochemistry

Background:

• High-throughput organic synthesis necessitates parallel advances in metabolic screening capabilities.
• Liquid chromatography/tandem mass spectrometry (LC/MS/MS) is the preferred analytical technique for its sensitivity and selectivity in high-throughput screening.
• Traditional LC/MS/MS method development can be a bottleneck in early drug discovery workflows.

Purpose of the Study:

• To develop an automated system for high-throughput metabolic screening to support early drug discovery.
• To reduce the time and complexity associated with LC/MS/MS method development for diverse compound libraries.
• To enable efficient analysis of in vitro assays such as microsomal stability and protein binding.

Main Methods:

• Integration of a robotic system for automated in vitro incubations.
• Utilization of commercially available software for automated MS/MS method development.
• Development of a generic, fast liquid chromatography (LC) gradient and mass spectrometry (MS) conditions suitable for a broad range of compounds.

Main Results:

• Successful implementation of an automated LC/MS/MS system for high-throughput screening.
• Demonstrated efficiency in minimizing method development time and data analysis.
• The system effectively supported various in vitro screening assays crucial for early drug discovery.

Conclusions:

• The developed automated system significantly enhances the throughput of metabolic screening.
• This approach streamlines early drug discovery by providing rapid and reliable analytical data.
• The generic LC/MS/MS conditions offer a versatile solution for analyzing diverse chemical entities.