Frequent hitters: nuisance artifacts in high-throughput screening.

Area of Science:

• Drug discovery and development
• Medicinal chemistry
• Computational toxicology

Background:

• Frequent hitters (FHs) pose a significant challenge in early drug discovery.
• FHs are compounds that exhibit non-specific binding or cause false positives due to assay interferences.

Purpose of the Study:

• To review the mechanisms of various FH types.
• To survey experimental and computational methods for FH identification.
• To discuss the rational application of FH filters in drug discovery.

Main Methods:

• Literature review of FH mechanisms.
• Survey of experimental detection techniques.
• Review of computational prediction models for FH identification.

Main Results:

• Categorization of FHs into aggregators, spectroscopic interference compounds, chemical reactive compounds, and promiscuous compounds.
• Overview of common experimental assays for FH detection.
• Discussion of computational approaches for predicting and filtering FHs.

Conclusions:

• Understanding FH mechanisms is crucial for mitigating false positives.
• A combination of experimental and computational methods enhances FH identification.
• Rational application of FH filters can significantly improve early drug discovery efficiency.