In Silico QT and APD prolongation assay for early screening of drug-induced proarrhythmic risk

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Romero, Lucia
• dc.contributor.author Cano, Jordi
• dc.contributor.author Gomis-Tena, Julio
• dc.contributor.author Trenor, Beatriz
• dc.contributor.author Sanz, Ferran
• dc.contributor.author Pastor Maeso, Manuel
• dc.contributor.author Saiz, Javier
• dc.date.accessioned 2018-11-14T08:29:48Z
• dc.date.available 2018-11-14T08:29:48Z
• dc.date.issued 2018
• dc.description.abstract 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. , 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 ( IKs and IKr, respectively) and the L-type calcium current ( ICaL) 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.
• dc.description.sponsorship L.R., J.C., J.G., B.T., J.S.: This work was partially supported by the Direccion General de Política Cientifíca 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.format.mimetype application/pdf
• dc.identifier.citation Romero L, Cano J, Gomis-Tena J, Trenor B, Sanz F, Pastor M et al. In Silico QT and APD prolongation assay for early screening of drug-induced proarrhythmic risk. J Chem Inf Model. 2018 Apr 23;58(4):867-78. DOI: 10.1021/acs.jcim.7b00440
• dc.identifier.doi http://dx.doi.org/10.1021/acs.jcim.7b00440
• dc.identifier.issn 1549-9596
• dc.identifier.uri http://hdl.handle.net/10230/35748
• dc.language.iso eng
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof Journal of Chemical Information and Modeling. 2018 Apr 23;58(4):867-78
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/115002
• dc.rights This is an open access article published under an ACS Author Choice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Medicaments -- Efectes fisiològics
• dc.title In Silico QT and APD prolongation assay for early screening of drug-induced proarrhythmic risk
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion