title: 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.
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.
authors.affiliation: 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.
authors.forename: Anwar
authors.initials: A
authors.lastname: Anwar-Mohamed
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Noskov
authors.affiliation: 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.
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.affiliation: 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.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D066126:Cardiotoxicity; D002478:Cells, Cultured; D016000:Cluster Analysis; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D008133:Long QT Syndrome; D056004:Molecular Dynamics Simulation; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D025341:Principal Component Analysis; D011487:Protein Conformation; D012680:Sensitivity and Specificity
chemical_list: D000998:Antiviral Agents; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers
keywords: Anti-HCV drugs; BMS-986094; Cardiotoxicity; Computational modelling; Docking; Ion channels; Predictive toxicology; hERG