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Toxicol Lett. 2014 Nov 4;230(3):382-92. doi: 10.1016/j.toxlet.2014.08.007. Epub 2014 Aug 13.

A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity.

Author information

1
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada; Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
2
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada.
3
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
4
Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
5
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
6
Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada; Department of Physics, University of Alberta, Edmonton, AB, Canada.
7
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. Electronic address: michael.houghton@ualberta.ca.

Abstract

Acquired cardiac long QT syndrome (LQTS) is a frequent drug-induced toxic event that is often caused through blocking of the human ether-á-go-go-related (hERG) K(+) ion channel. This has led to the removal of several major drugs post-approval and is a frequent cause of termination of clinical trials. We report here a computational atomistic model derived using long molecular dynamics that allows sensitive prediction of hERG blockage. It identified drug-mediated hERG blocking activity of a test panel of 18 compounds with high sensitivity and specificity and was experimentally validated using hERG binding assays and patch clamp electrophysiological assays. The model discriminates between potent, weak, and non-hERG blockers and is superior to previous computational methods. This computational model serves as a powerful new tool to predict hERG blocking thus rendering drug development safer and more efficient. As an example, we show that a drug that was halted recently in clinical development because of severe cardiotoxicity is a potent inhibitor of hERG in two different biological assays which could have been predicted using our new computational model.

KEYWORDS:

Anti-HCV drugs; BMS-986094; Cardiotoxicity; Computational modelling; Docking; Ion channels; Predictive toxicology; hERG

PMID:
25127758
DOI:
10.1016/j.toxlet.2014.08.007
[Indexed for MEDLINE]
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