When Does the IC50 Accurately Assess the Blocking Potency of a Drug?

[EN] Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-a-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is...

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Autores: Gomis-Tena Dolz, Julio|||0000-0002-1309-2368, Trenor Gomis, Beatriz Ana|||0000-0001-9166-6112, Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825, Romero Pérez, Lucia|||0000-0003-4605-8630, Brown, Brandon M., Cano, Jordi, Yang, Pei-Chi, Clancy, Colleen E.
Tipo de recurso: artículo
Fecha de publicación:2020
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:10251/160904
Acceso en línea:https://riunet.upv.es/handle/10251/160904
Access Level:acceso abierto
Palabra clave:Drug-induced arrhythmia
Cardiotoxicity
Computer modeling
Potassium channels
Modelization
IC50 measurement
HERG channels
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
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oai_identifier_str oai:riunet.upv.es:10251/160904
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
title When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
spellingShingle When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Drug-induced arrhythmia
Cardiotoxicity
Computer modeling
Potassium channels
Modelization
IC50 measurement
HERG channels
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
title_short When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
title_full When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
title_fullStr When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
title_full_unstemmed When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
title_sort When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
dc.creator.none.fl_str_mv Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Trenor Gomis, Beatriz Ana|||0000-0001-9166-6112
Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825
Romero Pérez, Lucia|||0000-0003-4605-8630
Brown, Brandon M.
Cano, Jordi
Yang, Pei-Chi
Clancy, Colleen E.
author Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
author_facet Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Trenor Gomis, Beatriz Ana|||0000-0001-9166-6112
Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825
Romero Pérez, Lucia|||0000-0003-4605-8630
Brown, Brandon M.
Cano, Jordi
Yang, Pei-Chi
Clancy, Colleen E.
author_role author
author2 Trenor Gomis, Beatriz Ana|||0000-0001-9166-6112
Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825
Romero Pérez, Lucia|||0000-0003-4605-8630
Brown, Brandon M.
Cano, Jordi
Yang, Pei-Chi
Clancy, Colleen E.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv 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
Generalitat Valenciana
National Institutes of Health, EEUU
Universitat Politècnica de València
Ministerio de Economía y Competitividad
Repositorio Institucional de la Universitat Politècnica de València Riunet
dc.subject.none.fl_str_mv Drug-induced arrhythmia
Cardiotoxicity
Computer modeling
Potassium channels
Modelization
IC50 measurement
HERG channels
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
topic Drug-induced arrhythmia
Cardiotoxicity
Computer modeling
Potassium channels
Modelization
IC50 measurement
HERG channels
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
description [EN] Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-a-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC50 that will help to decide whether the IC50 is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC50 protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC50 value, which suggests that the IC50 could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC50 values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC50 and minimum IC50 depended on the drug, which complicates the definition of a "standard" protocol to minimize the influence of the stimulation protocol on the IC50 measurement in safety pharmacology. As a conclusion, we propose the adoption of our threeprotocol IC50 assay to estimate the potency to block hERG in vitro. If the IC50 values obtained for a compound are similar, then the IC50 could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-03-23
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/10251/160904
url https://riunet.upv.es/handle/10251/160904
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Universitat Politècnica de València https://doi.org/10.13039/501100004233 PAID-06-18
National Institutes of Health, EEUU https://doi.org/10.13039/100000002 1R01HL128537-01A1 In silico Safety Pharmacology
Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 DPI2015-69125-R SIMULACION COMPUTACIONAL PARA LA PREDICCION PERSONALIZADA DE LOS EFECTOS DE LOS FARMACOS SOBRE LA ACTIVIDAD CARDIACA
Generalitat Valenciana https://doi.org/10.13039/501100003359 PROMETEO%2F2016%2F088 MODELOS COMPUTACIONALES PERSONALIZADOS MULTI-ESCALA PARA LA OPTIMIZACION DEL DIAGNOSTICO Y TRATAMIENTO DE ARRITMIAS CARDIACAS (PERSONALISED DIGITAL HEART)
Universitat Politècnica de València https://doi.org/10.13039/501100004233 SP20180274
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reserva de todos los derechos
http://rightsstatements.org/vocab/InC/1.0/
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
Reserva de todos los derechos
http://rightsstatements.org/vocab/InC/1.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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
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spelling When Does the IC50 Accurately Assess the Blocking Potency of a Drug?Gomis-Tena Dolz, Julio|||0000-0002-1309-2368Trenor Gomis, Beatriz Ana|||0000-0001-9166-6112Saiz Rodríguez, Francisco Javier|||0000-0002-9850-0825Romero Pérez, Lucia|||0000-0003-4605-8630Brown, Brandon M.Cano, JordiYang, Pei-ChiClancy, Colleen E.Drug-induced arrhythmiaCardiotoxicityComputer modelingPotassium channelsModelizationIC50 measurementHERG channelsClass III drugsProarrhythmic riskDrug safetyTECNOLOGIA ELECTRONICA[EN] Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-a-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC50 that will help to decide whether the IC50 is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC50 protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC50 value, which suggests that the IC50 could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC50 values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC50 and minimum IC50 depended on the drug, which complicates the definition of a "standard" protocol to minimize the influence of the stimulation protocol on the IC50 measurement in safety pharmacology. As a conclusion, we propose the adoption of our threeprotocol IC50 assay to estimate the potency to block hERG in vitro. If the IC50 values obtained for a compound are similar, then the IC50 could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.This work was partially supported by the Direccion General de Polit ' ica Cientifica de la Generalitat Valenciana (PROMETEU2016/088), Ministerio de Economia y Competitividad, and Fondo Europeo de Desarrollo Regional (FEDER) DPI2015-69125-R (MINECO/FEDER, UE) as well as Ayuda a Primeros Proyectos de Investigacion (PAID-06-18), Vicerrectorado de Investigacion. Innovacion y Transferencia de la Universitat Politecnica de Valencia (UPV), Valencia, Spain. The research was also supported by the National Institutes of Health 1R01HL128537-01A1American Chemical SocietyDepartamento de Ingeniería ElectrónicaEscuela Técnica Superior de Ingeniería Aeroespacial y Diseño IndustrialEscuela Técnica Superior de Ingeniería IndustrialCentro de Investigación e Innovación en BioingenieríaGeneralitat ValencianaNational Institutes of Health, EEUUUniversitat Politècnica de ValènciaMinisterio de Economía y CompetitividadRepositorio Institucional de la Universitat Politècnica de València Riunet20202020-03-23journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://riunet.upv.es/handle/10251/160904reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valénciainstname:Universitat Politècnica de València (UPV)InglésengUniversitat Politècnica de València https://doi.org/10.13039/501100004233 PAID-06-18National Institutes of Health, EEUU https://doi.org/10.13039/100000002 1R01HL128537-01A1 In silico Safety PharmacologyMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 DPI2015-69125-R SIMULACION COMPUTACIONAL PARA LA PREDICCION PERSONALIZADA DE LOS EFECTOS DE LOS FARMACOS SOBRE LA ACTIVIDAD CARDIACAGeneralitat Valenciana https://doi.org/10.13039/501100003359 PROMETEO%2F2016%2F088 MODELOS COMPUTACIONALES PERSONALIZADOS MULTI-ESCALA PARA LA OPTIMIZACION DEL DIAGNOSTICO Y TRATAMIENTO DE ARRITMIAS CARDIACAS (PERSONALISED DIGITAL HEART)Universitat Politècnica de València https://doi.org/10.13039/501100004233 SP20180274open accesshttp://purl.org/coar/access_right/c_abf2Reserva de todos los derechoshttp://rightsstatements.org/vocab/InC/1.0/info:eu-repo/semantics/openAccessoai:riunet.upv.es:10251/1609042026-06-13T07:49:27Z
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