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Structure-Promiscuity Relationship Puzzles—Extensively Assayed Analogs with Large Differences in Target Annotations

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Abstract

Publicly available screening data were systematically searched for extensively assayed structural analogs with large differences in the number of targets they were active against. Screening compounds with potential chemical liabilities that may give rise to assay artifacts were identified and excluded from the analysis. “Promiscuity cliffs” were frequently identified, defined here as pairs of structural analogs with a difference of at least 20 target annotations across all assays they were tested in. New assay indices were introduced to prioritize cliffs formed by screening compounds that were extensively tested in comparably large numbers of assays including many shared assays. In these cases, large differences in promiscuity degrees were not attributable to differences in assay frequency and/or lack of assay overlap. Such analog pairs have high priority for further exploring molecular origins of multi-target activities. Therefore, these promiscuity cliffs and associated target annotations are made freely available. The corresponding analogs often represent equally puzzling and interesting examples of structure-promiscuity relationships.

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Acknowledgements

We thank OpenEye Scientific Software, Inc. for a free academic license of the OpenEye Toolkits.

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Authors and Affiliations

  1. Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2, 53113, Bonn, Germany

    Ye Hu, Swarit Jasial, Erik Gilberg & Jürgen Bajorath

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  1. Ye Hu
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  2. Swarit Jasial
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  3. Erik Gilberg
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  4. Jürgen Bajorath
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Correspondence to Jürgen Bajorath.

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Hu, Y., Jasial, S., Gilberg, E. et al. Structure-Promiscuity Relationship Puzzles—Extensively Assayed Analogs with Large Differences in Target Annotations. AAPS J 19, 856–864 (2017). https://doi.org/10.1208/s12248-017-0066-8

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