Journal of Computer-Aided Molecular Design

, Volume 21, Issue 4, pp 189–206 | Cite as

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

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


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.


hERG Hierarchical PLS modelling Onion design QSAR 



The authors thank the following from Safety Pharmacology, Astrazeneca Pharmaceuticals, Department of Safety Assessment, Alderley Park, Macclesfield, Cheshire SKN 4TG, U.K.: B.G. Small, M.H. Bridgeland-Taylor, A.J. Woods and A. Harmer for generating the IonWorks™ HT Data that form the basis of this work and C.E. Pollard for discussions around the biological aspects of this manuscripts


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Claire L. Gavaghan
    • 1
    Email author
  • 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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