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

PLoS Comput Biol. 2021 Aug 12;17(8):e1009233. doi: 10.1371/journal.pcbi.1009233. eCollection 2021 Aug.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Amino Acid Substitution
  • Animals
  • Anti-Arrhythmia Agents / administration & dosage
  • Arrhythmias, Cardiac / drug therapy*
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology
  • Computational Biology
  • Drug Combinations
  • Drug Design
  • Drug Therapy, Combination / methods
  • ERG1 Potassium Channel / drug effects*
  • ERG1 Potassium Channel / genetics*
  • ERG1 Potassium Channel / physiology
  • Heart Conduction System / abnormalities*
  • Heart Conduction System / physiopathology
  • Heart Defects, Congenital / drug therapy*
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / physiopathology
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / physiology
  • Models, Cardiovascular*
  • Mutation, Missense
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / physiology
  • Rabbits

Substances

  • Anti-Arrhythmia Agents
  • Drug Combinations
  • ERG1 Potassium Channel
  • KCNH2 protein, human

Supplementary concepts

  • Short QT Syndrome 1

Grants and funding

KJ and AT were supported by the Research Council of Norway funded IDENTIPHY project #309871/E50. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.