A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.

Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel ca...

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Autores principales:	Karoline Horgmo Jæger, Andrew G Edwards, Wayne R Giles, Aslak Tveito
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6bfa1b88237b4a23a733a16602288d87
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spelling	oai:doaj.org-article:6bfa1b88237b4a23a733a16602288d872021-12-02T19:58:05ZA computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.1553-734X1553-735810.1371/journal.pcbi.1009233https://doaj.org/article/6bfa1b88237b4a23a733a16602288d872021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009233https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on individual ion currents, our aim is to compute optimal combinations that can 'repair' the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type counterparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K+ channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the 'composition' of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.Karoline Horgmo JægerAndrew G EdwardsWayne R GilesAslak TveitoPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009233 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Karoline Horgmo Jæger Andrew G Edwards Wayne R Giles Aslak Tveito A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.
description	Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on individual ion currents, our aim is to compute optimal combinations that can 'repair' the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type counterparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K+ channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the 'composition' of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.
format	article
author	Karoline Horgmo Jæger Andrew G Edwards Wayne R Giles Aslak Tveito
author_facet	Karoline Horgmo Jæger Andrew G Edwards Wayne R Giles Aslak Tveito
author_sort	Karoline Horgmo Jæger
title	A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.
title_short	A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.
title_full	A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.
title_fullStr	A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.
title_full_unstemmed	A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.
title_sort	computational method for identifying an optimal combination of existing drugs to repair the action potentials of sqt1 ventricular myocytes.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/6bfa1b88237b4a23a733a16602288d87
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A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.

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