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Biased retrieval of chemical series in receptor-based virtual screening

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Abstract

Using the kinases in the DUD dataset and an in-house HTS dataset from PI3K-γ, receptor-based virtual screening experiments were performed using Glide SP docking. While significant enrichments were observed for eight of the nine targets in the set, more detailed analyses highlighted that much of the early enrichment (10–80%) is the result of retrieval of a single cluster of active compounds. This biased retrieval was not necessarily due to early enrichment of the cluster containing the co-crystallized ligand. Virtual screening validation studies could thus benefit from including cluster-based analyses to assess enrichment of diverse chemotypes.

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Acknowledgments

The authors thank David C. Thompson, Brajesh K. Rai, J. Christian Baber, Kristi Yi Fan, and Yongbo for participating in the virtual screening studies using the DUD.

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Author notes

  1. Natasja Brooijmans & Jason B. Cross

    Present address: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA

Authors and Affiliations

  1. Wyeth Research, Chemical Sciences, 401 N. Middletown Road, Pearl River, NY, 10965, USA

    Natasja Brooijmans

  2. Wyeth Research, Chemical Sciences, 500 Arcola Road, Collegeville, PA, 19426, USA

    Jason B. Cross

  3. Wyeth Research, Chemical Sciences, 865 Ridge Road, Princeton, NJ, 08543, USA

    Christine Humblet

  4. Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA

    Jason B. Cross

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  1. Natasja Brooijmans
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Correspondence to Natasja Brooijmans.

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Natasja Brooijmans and Jason B. Cross contributed equally to this work.

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Brooijmans, N., Cross, J.B. & Humblet, C. Biased retrieval of chemical series in receptor-based virtual screening. J Comput Aided Mol Des 24, 1053–1062 (2010). https://doi.org/10.1007/s10822-010-9394-9

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  • DOI: https://doi.org/10.1007/s10822-010-9394-9

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