Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration

[EN] 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 stat...

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Autores: Escobar-Ropero, Fernando|||0000-0001-7602-447X, Gomis-Tena Dolz, Julio|||0000-0002-1309-2368, Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825, Romero Pérez, Lucia|||0000-0003-4605-8630, Friis, Soren, Adly, Nouran, Brinkwirth, Nina, Klaerke, Dan A., Stoelzle-Feix, Sonja
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Politècnica de València (UPV)
Repositorio:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
Idioma:inglés
OAI Identifier:oai:riunet.upv.es:10251/220134
Acceso en línea:https://riunet.upv.es/handle/10251/220134
Access Level:acceso abierto
Palabra clave:HERG Blockers
CiPA
Mathematical Models
Binding mechanism
Automated Patch Clamp
id ES_55e8695f8fca0bd27c42e90ba9e26708
oai_identifier_str oai:riunet.upv.es:10251/220134
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
title Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
spellingShingle Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
Escobar-Ropero, Fernando|||0000-0001-7602-447X
HERG Blockers
CiPA
Mathematical Models
Binding mechanism
Automated Patch Clamp
title_short Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
title_full Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
title_fullStr Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
title_full_unstemmed Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
title_sort Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration
dc.creator.none.fl_str_mv Escobar-Ropero, Fernando|||0000-0001-7602-447X
Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825
Romero Pérez, Lucia|||0000-0003-4605-8630
Friis, Soren
Adly, Nouran
Brinkwirth, Nina
Klaerke, Dan A.
Stoelzle-Feix, Sonja
author Escobar-Ropero, Fernando|||0000-0001-7602-447X
author_facet Escobar-Ropero, Fernando|||0000-0001-7602-447X
Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825
Romero Pérez, Lucia|||0000-0003-4605-8630
Friis, Soren
Adly, Nouran
Brinkwirth, Nina
Klaerke, Dan A.
Stoelzle-Feix, Sonja
author_role author
author2 Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825
Romero Pérez, Lucia|||0000-0003-4605-8630
Friis, Soren
Adly, Nouran
Brinkwirth, Nina
Klaerke, Dan A.
Stoelzle-Feix, Sonja
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Centro de Investigación e Innovación en Bioingeniería
Departamento de Ingeniería Electrónica
Escuela Técnica Superior de Ingeniería Aeroespacial y Diseño Industrial
Escuela Técnica Superior de Ingeniería Industrial
GENERALITAT VALENCIANA
AGENCIA ESTATAL DE INVESTIGACION
European Regional Development Fund
European Commission
Universitat Politècnica de València
MINISTERIO DE UNIVERSIDADES E INVESTIGACION
Repositorio Institucional de la Universitat Politècnica de València Riunet
dc.subject.none.fl_str_mv HERG Blockers
CiPA
Mathematical Models
Binding mechanism
Automated Patch Clamp
topic HERG Blockers
CiPA
Mathematical Models
Binding mechanism
Automated Patch Clamp
description [EN] 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-09-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://riunet.upv.es/handle/10251/220134
url https://riunet.upv.es/handle/10251/220134
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2022-140553OB-C41 MODELADO Y SIMULACION DE LA MEDICINA DE PRECISION EN CARDIOLOGIA
European Commission https://doi.org/10.13039/501100000780 H2020 101016496 Simulation of Cardiac Devices & Drugs for in-silico Testing and Certification
Ministerio de Universidades MIU FPU19%2F02200 MODELOS IN SILICO PARA EL ESTUDIO DEL EFECTO DE FÁRMACOS EN EL CORAZÓN. BIOMARCADORES PARA LA PREDICCIÓN DE LA EFICACIA Y SEGURIDAD DE NUEVOS FÁRMACOS.
Generalitat Valenciana https://doi.org/10.13039/501100003359 PROMETEO%2F2020%2F043 MODELOS IN-SILICO MULTI-FISICOS Y MULTI-ESCALA DEL CORAZON PARA EL DESARROLLO DE NUEVOS METODOS DE PREVENCION, DIAGNOSTICO Y TRATAMIENTO EN MEDICINA PERSONALIZADA (HEART IN-SILICO MODELS)
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reconocimiento - No comercial - Sin obra derivada (by-nc-nd)
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reconocimiento - No comercial - Sin obra derivada (by-nc-nd)
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
instname:Universitat Politècnica de València (UPV)
instname_str Universitat Politècnica de València (UPV)
reponame_str RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
collection RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408341424340992
spelling Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential durationEscobar-Ropero, Fernando|||0000-0001-7602-447XGomis-Tena Dolz, Julio|||0000-0002-1309-2368Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825Romero Pérez, Lucia|||0000-0003-4605-8630Friis, SorenAdly, NouranBrinkwirth, NinaKlaerke, Dan A.Stoelzle-Feix, SonjaHERG BlockersCiPAMathematical ModelsBinding mechanismAutomated Patch Clamp[EN] 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.This work was funded by the Spanish Ministerio de Ciencia, Innovacion y Universidades [grant "Formacion de Profesorado Universitario" FPU19/02200; grant PID2022-140553OB-C41 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU]; the European Union's Horizon 2020 research and innovation program [grant agreement No. 101016496 (SimCardioTest) ] and the Direccion General de Politica Cientifica de la Generalitat Valenciana [grant PROMETEO/2020/043]. SF, NA, NB and SS are employed by Nanion Technologies, the manufacturer of the SyncroPatch 384i used to obtain the experimental data of this manuscript. The dynamic models of the I Kr blockers have been generated in accordance with the technology protected by PCT/ES2023/070195 (patent pending).ElsevierCentro de Investigación e Innovación en BioingenieríaDepartamento de Ingeniería ElectrónicaEscuela Técnica Superior de Ingeniería Aeroespacial y Diseño IndustrialEscuela Técnica Superior de Ingeniería IndustrialGENERALITAT VALENCIANAAGENCIA ESTATAL DE INVESTIGACIONEuropean Regional Development FundEuropean CommissionUniversitat Politècnica de ValènciaMINISTERIO DE UNIVERSIDADES E INVESTIGACIONRepositorio Institucional de la Universitat Politècnica de València Riunet20242024-09-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://riunet.upv.es/handle/10251/220134reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valénciainstname:Universitat Politècnica de València (UPV)InglésengAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2022-140553OB-C41 MODELADO Y SIMULACION DE LA MEDICINA DE PRECISION EN CARDIOLOGIAEuropean Commission https://doi.org/10.13039/501100000780 H2020 101016496 Simulation of Cardiac Devices & Drugs for in-silico Testing and CertificationMinisterio de Universidades MIU FPU19%2F02200 MODELOS IN SILICO PARA EL ESTUDIO DEL EFECTO DE FÁRMACOS EN EL CORAZÓN. BIOMARCADORES PARA LA PREDICCIÓN DE LA EFICACIA Y SEGURIDAD DE NUEVOS FÁRMACOS.Generalitat Valenciana https://doi.org/10.13039/501100003359 PROMETEO%2F2020%2F043 MODELOS IN-SILICO MULTI-FISICOS Y MULTI-ESCALA DEL CORAZON PARA EL DESARROLLO DE NUEVOS METODOS DE PREVENCION, DIAGNOSTICO Y TRATAMIENTO EN MEDICINA PERSONALIZADA (HEART IN-SILICO MODELS)open accesshttp://purl.org/coar/access_right/c_abf2Reconocimiento - No comercial - Sin obra derivada (by-nc-nd) http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:riunet.upv.es:10251/2201342026-06-13T07:49:27Z
score 15,81155

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