Stratified high-throughput screening sets enable flexible screening strategies from a single plated collection

Area of Science:

• Drug discovery and development
• Chemical biology
• High-throughput screening

Background:

• Large corporate compound collections pose challenges for high-throughput screening (HTS) due to time and cost constraints associated with compound picking and plating.
• Traditional methods for creating smaller screening sets from vast libraries are often inefficient and may not represent the full chemical diversity.

Purpose of the Study:

• To present a novel stratified screening deck and plating design for efficiently utilizing very large corporate compound collections in HTS.
• To demonstrate a method for flexible, on-the-fly downsizing of screening sets from a master deck without physical re-picking.
• To validate that downsized stratified sets yield superior results and maximize returns compared to randomly selected subsets.

Main Methods:

• Development of a stratified screening deck design for large compound libraries.
• Implementation of a plating strategy allowing flexible, on-the-fly downsizing of screening sets.
• Comparative analysis of results from stratified downsized sets versus randomly picked subsets of equivalent size.

Main Results:

• The stratified screening deck allows for rapid and flexible downsizing of screening sets from master plates.
• Downsized stratified sets demonstrated superior performance and maximized returns compared to random subsets of the same size.
• The plating design ensures structural diversity and favorable compound properties are maintained in downsized subsets.

Conclusions:

• The proposed stratified plating design offers an economical and rapid method for generating diverse screening subsets from large compound collections.
• This approach enables substantial cost savings in screening campaigns by allowing flexible set size adjustments on a per-screen basis.
• The global implementation at AstraZeneca since 2009 validates the practical utility and efficiency of this strategy for large-scale drug discovery efforts.