Journal of Computer-Aided Molecular Design

, Volume 21, Issue 4, pp 189–206

Development, interpretation and temporal evaluation of a global QSAR of hERG electrophysiology screening data

  • Claire L. Gavaghan
  • Catrin Hasselgren Arnby
  • Niklas Blomberg
  • Gert Strandlund
  • Scott Boyer
Original paper

Abstract

A ‘global’ model of hERG K+ channel was built to satisfy three basic criteria for QSAR models in drug discovery: (1) assessment of the applicability domain, (2) assuring that model decisions can be interpreted by medicinal chemists and (3) assessment of model performance after the model was built. A combination of D-optimal onion design and hierarchical partial least squares modelling was applied to construct a global model of hERG blockade in order to maximize the applicability domain of the model and to enhance its interpretability. Additionally, easily interpretable hERG specific fragment-based descriptors were developed. Model performance was monitored, throughout a time period of 15 months, after model implementation. It was found that after this time duration a greater proportion of molecules were outside the model’s applicability domain and that these compounds had a markedly higher average prediction error than those from molecules within the model’s applicability domain. The model’s predictive performance deteriorated within 4 months after building, illustrating the necessity of regular updating of global models within a drug discovery environment.

Keywords

hERG Hierarchical PLS modelling Onion design QSAR 

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Claire L. Gavaghan
    • 1
  • Catrin Hasselgren Arnby
    • 1
  • Niklas Blomberg
    • 2
  • Gert Strandlund
    • 3
  • Scott Boyer
    • 1
  1. 1.Computational Toxicology, Safety AssessmentAstraZeneca R&DMolndalSweden
  2. 2.Global DECS Computational ChemistryAstraZeneca R&DMolndalSweden
  3. 3.Lead GenerationAstraZeneca R&DMolndalSweden

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