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Chemical libraries

How dark is HTS dark matter?

Nature Chemical Biology volume 11, pages 904–905 (2015)Cite this article

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Selecting compounds for the chemical library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many molecules in the Novartis and NIH Molecular Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compounds of interest.

The virtual chemical space of lead-like molecules contains more than 1030 possible compounds2; of this vast universe 'only' ∼90 million small molecules are commercially available (http://zinc.docking.org/). The universe of biomolecular binding pockets of future interest is orders of magnitude smaller but very much unknown, and the methods to predict computationally what molecules will bind to these pockets are not reliable enough to make 'genie-grade' selections. Budget limitations thus far have afforded collections ranging from 10,000 up to 5 million chemicals in different academic and industrial labs. Much has been written about how to rationally select (and design) chemicals for screening on the basis of molecular properties, chemical diversity or known bioactivity3, and there is also a wealth of information about what chemicals should be avoided because of reactivity or promiscuity4; but what to do about the inactive molecules has so far been less well covered in the literature.

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Figure 1: A brief tale of the origin and fate of HTS libraries.

Marina Coral Spence/Nature Publishing Group

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  1. Ricardo Macarron is in the Department of Target Sciences, GlaxoSmithKline R&D, Collegeville, Pennsylvania, USA.,

    Ricardo Macarron

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  1. Ricardo Macarron
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Correspondence to Ricardo Macarron.

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Macarron, R. How dark is HTS dark matter?. Nat Chem Biol 11, 904–905 (2015). https://doi.org/10.1038/nchembio.1937

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