SPREAD—exploiting chemical features that cause differential activity behavior

Authors

  • Josef Scheiber,

    Corresponding author
    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    • Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
    • Novartis Pharma AG, NITAS/Text Mining Services, Forum 1, 4002 Basel, Switzerland

  • Jeremy L. Jenkins,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Andreas Bender,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
    • Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

  • Mariusz Milik,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Dmitri Mikhailov,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Sai Chetan K. Sukuru,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Ben Cornett,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Steven Whitebread,

    1. Novartis Institutes for Biomedical Research, Preclinical Safety Profiling, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Laszlo Urban,

    1. Novartis Institutes for Biomedical Research, Preclinical Safety Profiling, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • John W. Davies,

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author
  • Meir Glick

    1. Novartis Institutes for Biomedical Research, Lead Discovery Informatics, 250 Massachussetts Avenue, Cambridge, MA
    Search for more papers by this author

Abstract

We present a novel generic method to better understand the divergent activities of molecules that often occur in orthogonal assays. The newly developed simple prediction of activity differences (SPREAD) method directly aims to model and understand the differences compounds exhibit when tested in two or more assays. By transforming the activity values from the assays into meta-categories (specifically defined for datasets under scrutiny), statistical models can be trained directly on the qualitative differences between assays. This contributes heavily toward a tangible understanding of molecular assay selectivity. Although ensembles of models could be used alternatively to predict compounds that score highly in one assay and low in another, the advantage of the SPREAD approach is that the chemical features influencing assay differences are parsed out immediately as a consequence of training the model on the coincident assay differences. By training the model that describes the difference between two or more assays, molecular substructures that are responsible for assay selectivity can be parsed out. The method was validated by using four challenging datasets. Copyright © 2009 Wiley Periodicals, Inc., Statistical Analysis and Data Mining 2: 115-122, 2009

Ancillary