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

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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.

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Acknowledgements

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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Correspondence to Claire L. Gavaghan.

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Gavaghan, C.L., Arnby, C.H., Blomberg, N. et al. Development, interpretation and temporal evaluation of a global QSAR of hERG electrophysiology screening data. J Comput Aided Mol Des 21, 189–206 (2007). https://doi.org/10.1007/s10822-006-9095-6

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  • DOI: https://doi.org/10.1007/s10822-006-9095-6

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