Dynamic Dofetilide-hERG Channel Model Considering Preferential State Binding and Trapping Properties

Assessment of cardiotoxicity is crucial in the development of new compounds and understandingbinding dynamics is important to study drug effects.We previously developed computational pipeline for generating Markovian drug-hERG channel models that reproduce binding properties.We have tested our methodology with the real IKr blocker dofetilide.Experiments were conducted using hERG transfected HEK cells and the Nanion SyncroPatch 384i.We applied three voltage clamp protocols, named P0, P40 and P-80, to generate the model.A unique IC50 value was also estimated using the CiPA ramp protocol and the model was tested with the Milnes protocol.The model accurately replicates the experimental data recordings with our protocols and the IC50 value is in accordance with the available literature.The model also resembles the behavior observed with the Milnes protocol.We show an experimental proof of concept of a novel methodology for generating dynamic drug models obtained with simple voltage clamp protocols that may constitute a marked improvement in cardiac safety assessment.