2026-10-15T17:49:23Zhttps://riunet.upv.es/server/oai/request

oai:riunet.upv.es:10251/2048222026-06-25T12:01:39Zcom_10251_11198col_10251_55048col_10251_9185openaire_data

Experimentally Validated Modeling of Dynamic Drug-hERG Channel Interactions Reproducing the Binding Mechanisms and its Importance in Action Potential Duration Escobar-Ropero, Fernando Gomis-Tena Dolz, Julio Saiz Rodríguez, Francisco Javier Romero Pérez, Lucia Friis, Soren Adly, Nouran Brinkwirth, Nina Arne Klaerke, Dan Stoelzle-Feix, Sonja Departamento de Ingeniería Electrónica Escuela Técnica Superior de Ingeniería Aeroespacial y Diseño Industrial Escuela Técnica Superior de Ingeniería Industrial Centro de Investigación e Innovación en Bioingeniería hERG Blockers Comprehensive In Vitro Proarrhythmia Assay (CiPA) Mathematical models Binding mechanism Automated patch clamp Cardiac cells Drug effects Mathematical modelling Computational simulation Data is structured in the format provided by Nanion SyncroPatch software. The folder structure is named after each compound tested, inside there is one folder per each of the three protocols used. Data is stored in JSON files containing the information of the experiment. Background and Objective: Assessment of drug cardiotoxicity is critical in the development of new compounds and modeling of drug-binding dynamics to hERG can improve early cardiotoxicity assessment. We previously developed a methodology to generate Markovian models reproducing preferential state-dependent binding properties, trapping dynamics and the onset of IKr block using simple voltage clamp protocols. Here, we test this methodology with real IKr blockers and investigate the impact of drug dynamics on action potential prolongation. Methods: Experiments were performed on HEK cells stably transfected with hERG and using the Nanion SyncroPatch 384i. Three protocols, P-80, P0 and P40, were applied to obtain the experimental data from the drugs and the Markovian models were generated using our pipeline. The corresponding static models were also generated and a modified version of the O´Hara-Rudy action potential model was used to simulate the action potential duration. Results: The experimental Hill plots and the onset of IKr block of ten compounds were obtained using our voltage clamp protocols and the models generated successfully mimicked these experimental data, unlike the CiPA dynamic models. Marked differences in APD prolongation were observed when drug effects were simulated using the dynamic models and the static models. Conclusions: These new dynamic models of ten well-known IKr blockers constitute a validation of our methodology to model dynamic drug–hERG channel interactions and highlight the importance of state-dependent binding, trapping dynamics and the time-course of IKr block to assess drug effects even at the steady-state. Escobar Ropero, F.; Friis, S.; Adly, N.; Brinkwirth, N.; Gomis-Tena Dolz, J.; Saiz Rodríguez, FJ.; Arne Klaerke, D.... (2024). Experimentally Validated Modeling of Dynamic Drug-hERG Channel Interactions Reproducing the Binding Mechanisms and its Importance in Action Potential Duration. Universitat Politècnica de València. https://doi.org/10.4995/Dataset/10251/204822 2024-06-08 Dataset info:eu-repo/semantics/submittedVersion https://riunet.upv.es/handle/10251/204822 info:doi:10.4995/Dataset/10251/204822 eng https://doi.org/10.1016/j.cmpb.2024.108293 info:eu-repo/grantAgreement/EC/H2020/101016496/EU/Simulation of Cardiac Devices & Drugs for in-silico Testing and Certification/SimCardioTest info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-140553OB-C41/ES/MODELADO Y SIMULACION DE LA MEDICINA DE PRECISION EN CARDIOLOGIA/ info:eu-repo/grantAgreement/MIU//FPU19%2F02200 info:eu-repo/grantAgreement/GVA//PROMETEO%2F2020%2F043 https://opendatacommons.org/licenses/by/1-0/ info:eu-repo/semantics/openAccess text/plain application/zip Universitat Politècnica de València