Molecular Determinants of Steroid Hormone and Drug Induced Arrhythmogenesis via hERG Channel Block

Abstract

Heart rhythm disturbances, such as long QT syndrome (LQTS), have been linked to mutations in cardiac ions channels, as well as unintended drug interactions with these channels. Female sex has been shown to be an independent risk factor for both inherited and acquired LQTS. Previous experimental studies and our recent multi-scale modeling (P.-C. Yang et al J. Physiol. 2017, 595: 4695) demonstrated that this phenomenon is likely related to differential levels of sex hormones (estradiol, progesterone and testosterone) playing opposite roles in pro-arrhythmia proclivities, exacerbating or mitigating effects of ion channel mutations or drug-induced blockade. In this study, we are focusing on hormone interactions with the human ether-a-go-go (hERG or Kv11.1) potassium channel, a major contributor to cardiac action potential repolarization and an anti-target for diverse drug molecules. Our preliminary electrophysiological measurements indicate channel-specific 15% Kv11.1 current blockade at physiological, low nM estradiol concentrations, and its combined additive effect with a potent hERG blocker, E-4031. We will extend these experiments to several combinations of steroid hormones and drugs with proclivity for sex-dependent arrhythmogenesis. We will use a recently published hERG structure (PDB id: 5VA1) and perform RosettaLigand molecular docking and atomistic molecular dynamics simulations to correlate experimental findings with specific ligand - channel interactions. Also, we will test if hormone and drug binding in the hERG cavity can synergistically increase their channel blocking affinities, as was suggested by our previous study. This methodology can be used for in silico assessment of drug cardiotoxicities and development of cardiac safe pharmaceuticals. Supported by National Institutes of Health NHLBI R01HL128537-02 and U01HL126273-02 grants as well as American Heart Association Pre-doctoral Fellowship (16PRE27260295), Western States Affiliate (to KRD).