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Streamlining bioactive molecular discovery through integration and automation

Nature Reviews Chemistry volume 2, pages 174–183 (2018)Cite this article

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Abstract

The discovery of bioactive small molecules is generally driven via iterative design–make–purify–test cycles. Automation is routinely harnessed at individual stages of these cycles to increase the productivity of drug discovery. Here, we describe recent progress to automate and integrate two or more adjacent stages within discovery workflows. Examples of such technologies include microfluidics, liquid-handling robotics and affinity-selection mass spectrometry. The value of integrated technologies is illustrated in the context of specific case studies in which modulators of targets, such as protein kinases, nuclear hormone receptors and protein–protein interactions, were discovered. We note that to maximize impact on the productivity of discovery, each of the integrated stages would need to have both high and matched throughput. We also consider the longer-term goal of realizing the fully autonomous discovery of bioactive small molecules through the integration and automation of all stages of discovery.

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Fig. 1: Current features and future aspirations in drug discovery workflows.
Fig. 2: Platforms for high-throughput reaction optimization to yield highly functionalized products.
Fig. 3: Platforms that integrate synthesis and biological evaluation to enable the discovery of bioactive small molecules.
Fig. 4: Integration of active learning, synthesis, purification and evaluation in the discovery of ABL kinase inhibitors.
Fig. 5: Activity-directed synthesis of androgen receptor agonists.

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Acknowledgements

The authors thank the Engineering and Physical Sciences Research Council (EPSRC; EP/N025652/1) for support.

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Nature Reviews Chemistry thanks D. Brown, D. Winkler and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK

    Shiao Chow, Samuel Liver & Adam Nelson

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S.C. and S.L. researched data for the article. All authors made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Adam Nelson.

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Chow, S., Liver, S. & Nelson, A. Streamlining bioactive molecular discovery through integration and automation. Nat Rev Chem 2, 174–183 (2018). https://doi.org/10.1038/s41570-018-0025-7

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