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A guide to drug discovery

Designing screens: how to make your hits a hit

Key Points

  • In recent years, the emphasis in high-throughput screening has shifted from increasing screening capacity to improving the quality of the resulting data.

  • This article discusses the issues that are crucial to successful screening, including:

  • What makes a good assay?

  • Types of screen and readouts

  • Compound selection by filtering screening libraries to remove compounds with undesirable properties, and focusing libraries to target types to enhance hit rates.

Abstract

The basic goal of small-molecule screening is the identification of chemically 'interesting' starting points for elaboration towards a drug. A number of innovative approaches for pursuing this goal have evolved, and the right approach is dictated by the target class being pursued and the capabilities of the organization involved. A recent trend in high-throughput screening has been to place less emphasis on the number of data points that can be produced, and to focus instead on the quality of the data obtained. Several computational and technological advances have aided in the selection of compounds for screening and widened the variety of assay formats available for screening. The effect on the efficiency of the screening process is discussed.

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Figure 1: Screening at higher concentration leads to greater structural diversity.
Figure 2: Examples of screening assays.
Figure 3
Figure 4: Examples of titration curves for compounds obtained from screening.
Figure 5: The effect of REOS (Rapid Elimination Of Swill) on screening efficiency.

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Correspondence to Mark Namchuk.

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FURTHER INFORMATION

Society for Biomolecular Screening

Glossary

HILL SLOPE

In the program Prism, the curves are fitted to the equation:

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Walters, W., Namchuk, M. Designing screens: how to make your hits a hit. Nat Rev Drug Discov 2, 259–266 (2003). https://doi.org/10.1038/nrd1063

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