The Use of Informer Sets in Screening: Perspectives on an Efficient Strategy to Identify New Probes

Area of Science:

• Drug Discovery
• Medicinal Chemistry
• Chemical Biology

Background:

• Small-molecule discovery relies on large screening campaigns, which are often costly and time-consuming.
• Inefficient screening due to low hit rates and sparse chemical space coverage limits success.
• The selection of appropriate screening collections is critical for efficient drug discovery.

Purpose of the Study:

• To discuss the utility of "informer sets" in small-molecule discovery.
• To demonstrate how informer sets can prioritize probe candidates.
• To promote the wider adoption of informer sets in drug discovery projects.

Main Methods:

• Assembling informer sets based on historical bioactivity, human exposure (repurposing), or chemical structure.
• Screening an informer set of 100,000 small molecules synthesized via diversity-oriented synthesis (DOS).
• Utilizing informer sets to identify early activity and focus on promising chemical scaffolds.

Main Results:

• Informer sets enable early identification of biological activity.
• Screening a focused informer set allows for more extensive testing of fewer chemical scaffolds.
• This approach enhances the efficiency and reduces the cost of small-molecule discovery.

Conclusions:

• Informer sets are a valuable strategy for prioritizing small molecules in discovery pipelines.
• Leveraging diverse data (bioactivity, exposure, structure) for informer set construction is effective.
• The informer set approach offers an elegant and economic solution to optimize screening efforts.