Maintaining a High-Quality Screening Collection: The GSK Experience

Area of Science:

• Pharmaceutical chemistry
• Chemical informatics

Background:

• Dimethyl sulfoxide (DMSO) is a common solvent for compound libraries in drug discovery.
• Compound instability during prolonged storage in DMSO is a known issue, impacting screening collection quality.
• GlaxoSmithKline (GSK) employs liquid chromatography-mass spectrometry (LC-MS) for quality control (QC) of its screening collection.

Purpose of the Study:

• To identify chemical substructures prone to degradation in DMSO using QC data.
• To develop data-driven filters for excluding unstable compounds from screening collections.
• To inform efficient, targeted compound collection clean-up initiatives.

Main Methods:

• Utilized a data-driven clustering algorithm to analyze LC-MS quality control data.
• Mined historical QC data to identify correlations between chemical substructures and compound degradation.
• Leveraged two decades of stability studies to define best practices for compound storage and handling.

Main Results:

• Identified specific chemical substructures associated with increased instability in DMSO.
• Developed new structural filters to proactively exclude compounds with degradation-prone motifs.
• Established insights into compound degradation under various storage and assay conditions.

Conclusions:

• Data mining of QC data provides a powerful tool for understanding and mitigating compound degradation.
• Proactive exclusion of unstable compounds enhances the quality and efficiency of high-throughput screening.
• Long-term stability studies are crucial for optimizing compound management and ensuring collection integrity.