title: In silico assessment of kinetics and state dependent binding properties of drugs causing acquired LQTS.
abstract: The Kv11.1 or hERG potassium channel is responsible for one of the major repolarising currents (IKr) in cardiac myocytes. Drug binding to hERG can result in reduction in IKr, action potential prolongation, acquired long QT syndrome and fatal cardiac arrhythmias. The current guidelines for pre-clinical assessment of drugs in development is based on the measurement of the drug concentration that causes 50% current block, i.e., IC50. However, drugs with the same apparent IC50 may have very different kinetics of binding and unbinding, as well as different affinities for the open and inactivated states of Kv11.1. Therefore, IC50 measurements may not reflect the true risk of drug induced arrhythmias. Here we have used an in silico approach to test the hypothesis that drug binding kinetics and differences in state-dependent affinity will influence the extent of cardiac action potential prolongation independent of apparent IC50 values. We found, in general that drugs with faster overall kinetics and drugs with higher affinity for the open state relative to the inactivated state cause more action potential prolongation. These characteristics of drug-hERG interaction are likely to be more arrhythmogenic but cannot be predicted by IC50 measurement alone. Our results suggest that the pre-clinical assessment of Kv11.1-drug interactions should include descriptions of the kinetics and state dependence of drug binding. Further, incorporation of this information into sophisticated in silico models should be able to better predict arrhythmia risk and therefore more accurately assess safety of new drugs in development.
authors.affiliation: Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, NSW 2052, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, NSW 2052, Australia.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Mann
authors.affiliation: Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Monique J
authors.initials: MJ
authors.lastname: Windley
authors.affiliation: Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, NSW 2052, Australia.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Imtiaz
authors.affiliation: Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, NSW 2052, Australia.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.affiliation: Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, NSW 2052, Australia. Electronic address: a.hill@victorchang.edu.au.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Hill
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000072237:ERG1 Potassium Channel; D026902:Potassium Channel Blockers
keywords: Acquired long QT syndrome; Arrhythmia; Kinetics; Kv11.1; Simulation; hERG