Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: Claire L Gavaghan, Catrin Hasselgren Arnby, Niklas Blomberg, Gert Strandlund, Scott Boyer

Journal, date & volume: J. Comput. Aided Mol. Des., 2007 Apr , 21, 189-206

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17384921

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.