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In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk

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In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk

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dc.contributor.author Romero Pérez, Lucia es_ES
dc.contributor.author Cano-García, Jordi es_ES
dc.contributor.author Gomis-Tena Dolz, Julio es_ES
dc.contributor.author Trenor Gomis, Beatriz Ana es_ES
dc.contributor.author Sanz, Ferran es_ES
dc.contributor.author Pastor, Manuel es_ES
dc.contributor.author Saiz Rodríguez, Francisco Javier es_ES
dc.date.accessioned 2019-04-07T20:06:30Z
dc.date.available 2019-04-07T20:06:30Z
dc.date.issued 2018 es_ES
dc.identifier.issn 1549-9596 es_ES
dc.identifier.uri http://hdl.handle.net/10251/119060
dc.description.abstract [EN] Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models (O'Hara, T., et al. PLos Comput. Biol. 2011, 7, e1002061) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current (I-Ks and I-Kr, respectively) and the L-type calcium current (I-CaL) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC50 based test. es_ES
dc.description.sponsorship L.R, J.C., J.G., B.T., J.S.: This work was partially supported by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEU2016/088) as well as Ministerio de Economia y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) DPI2015-69125-R (MINECO/FEDER, UE). F.S, M.P.: received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115002 (eTOX), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contributions.
dc.language Inglés es_ES
dc.publisher American Chemical Society es_ES
dc.relation IMI JOINT UNDERTAKING/115002 es_ES
dc.relation MINECODPI2015-69125-R es_ES
dc.relation GV/PROMETEO/2016/088 es_ES
dc.relation.ispartof Journal of Chemical Information and Modeling es_ES
dc.rights Reserva de todos los derechos es_ES
dc.subject.classification TECNOLOGIA ELECTRONICA es_ES
dc.title In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1021/acs.jcim.7b00440 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/115002/EU es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica es_ES
dc.description.bibliographicCitation Romero Pérez, L.; Cano-García, J.; Gomis-Tena Dolz, J.; Trenor Gomis, BA.; Sanz, F.; Pastor, M.; Saiz Rodríguez, FJ. (2018). In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk. Journal of Chemical Information and Modeling. 58(4):867-878. https://doi.org/10.1021/acs.jcim.7b00440 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion http://doi.org/10.1021/acs.jcim.7b00440 es_ES
dc.description.upvformatpinicio 867 es_ES
dc.description.upvformatpfin 878 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 58 es_ES
dc.description.issue 4 es_ES
dc.identifier.pmid 29547274
dc.relation.pasarela S\362649 es_ES
dc.contributor.funder Innovative Medicines Initiative es_ES
dc.contributor.funder Generalitat Valenciana es_ES
dc.contributor.funder Ministerio de Economía, Industria y Competitividad es_ES
dc.contributor.funder European Regional Development Fund
dc.contributor.funder European Commission


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