title: Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents.
abstract: The currently changing cardiac safety testing paradigm suggests, among other things, a shift towards using in silico models of cellular electrophysiology and assessment of a concomitant block of multiple ion channels. In this study, a set of four enhanced QSAR models have been developed: for the rapid delayed rectifying potassium current (IKr), slow delayed rectifying potassium current (IKs), peak sodium current (INa) and late calcium current (ICaL), predicting ion currents changes for the specific in vitro experiment from the 2D structure of the compounds. The models are a combination of both in vitro study parameters and physico-chemical descriptors, which is a novel approach in drug-ion channels interactions modeling. Their predictive power assessed in the enhanced, more demanding than standard procedure, 10-fold cross validation was reasonably high. Rough comparison with published pure in silico hERG interaction models shows that the quality of the model predictions does not differ from other models available in the public domain, however, it takes its advantage in accounting for inter-experimental settings variability. Developed models are implemented in the Cardiac Safety Simulator, a commercially available platform enabling the in vitro-in vivo extrapolation of the drugs proarrhythmic effect and ECG simulation. A more comprehensive assessment of the effects of the compounds on ion channels allows for making more informed decisions regarding the risk - and thus avoidance - of exclusion of potentially safe and effective drugs.
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Medical College, Jagiellonian University, Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiśniowska
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical College, Jagiellonian University, Krakow, Poland.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Mendyk
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical College, Jagiellonian University, Krakow, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Szlęk
authors.affiliation: Building and Structure Physics Division, Institute of Building Materials and Structures, Faculty of Civil Engineering, Cracow University of Technology, Krakow, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Medical College, Jagiellonian University, Krakow, Poland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Polak
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003198:Computer Simulation; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D007473:Ion Channels; D004364:Pharmaceutical Preparations
keywords: ANN; ICa; IKr; IKs; INa; QSAR model; cardiac ion channels; hERG; screening