Molecular simulations of state-specific drug interactions with multiple cardiac ion channels to reveal mechanisms of arrhythmogenesis.

Abstract

Unintended drug block of cardiac ion channels remains a major problem in drug development. The voltage-gated potassium channel KV11.1 also known as hERG is a major drug anti-target binding a diverse set of small molecule drugs that potently reduce the critical repolarizing current IKr. Many drugs that bind the hERG channel promote deadly arrythmias while some hERG blockers present significantly lower proarrhythmic risk. Two hypotheses were proposed to elucidate this discrepancy: (1) preferential drug binding to the inactivated state of the hERG channel confers greater proarrhythmic risk and (2) simultaneous drug binding to other cardiac ion channels can ameliorate the risk associated with hERG channel block. Here, we present a state-specific molecular modeling assessment of drug binding to different conformations of the hERG and voltage-gated sodium NaV1.5 and calcium CaV1.2 channels. We have developed structural models of these cardiac ion channels in open and inactivated conformations and performed all-atom molecular dynamics (MD) simulations to validate structural stabilities and assess ion conduction. Ligand docking was then performed using Site Identification by Ligand Competitive Saturation (SILCS), a pre-compute ensemble molecular docking technique. SILCS allows us to perform a high-throughput assessment of ligand binding affinities using molecular fragment energy maps derived from MD simulations of state-specific ion channel models. Bayesian machine learning was used to provide improved correlation of SILCS-computed affinities with experimental data. Using SILCS multi-ligand docking we also estimated interactions of drugs with sex hormones in the hERG channel pore to assess a potential molecular mechanism for an increased proarrhythmia risk in females. We aim to use SILCS computed state-specific drug affinity data to inform multi-scale functional kinetic models of cardiac electrophysiology to estimate emergent drug effects on the cardiac action potential and heart rhythm.