Prediction of hERG K+ blocking potency: Application of structural knowledge
- 29 October 2004
- journal article
- research article
- Published by Taylor & Francis in SAR and QSAR in Environmental Research
- Vol. 15 (5-6) , 399-411
- https://doi.org/10.1080/10629360412331297353
Abstract
Modelling of QT-prolongation has been performed using data for 19 structurally diverse hERG K+ channel blocking drugs taken from literature. The modelling used hydrophobicity corrected for ionisation (log D) and various 2D and 3D physico-chemical molecular descriptors. Stepwise regression produced a two parameter, interpretable and transparent QSAR with good statistical fit, including log D and the maximum diameter of molecules (D max). Two strategies were applied for model validation: (i) a scrambling procedure, i.e., training the total set of 19 chemicals after randomising the hERG K+ channel blocking activity data and (ii) use of external validation sets. Validation of the models showed them to be stable and statistically significant. The effect of molecular size on QT-prolongation side effect is discussed.Keywords
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