Drug-induced cardiotoxicity in the form of cardiac arrhythmia is a major problem in drug development, which has led to multiple drug candidate attritions from the development or marketplace. It has been attributed to a blockade of cardiac voltage-gated potassium channel Kv11.1, encoded by the human ether-a-go-go-related gene (hERG). However, not all hERG channel blocking drugs cause cardiac arrhythmias, leading to possible abandonment of safe and efficacious pharmaceuticals. We developed multi-scale modeling and simulation pipeline to predict arrhythmogenicity of drugs from their chemical structures. It starts from the development of optimized CHARMM general force field (CGENFF) models of drug molecules in different protonation states and using unbiased and enhanced sampling all-atom molecular dynamics (MD) simulations of their binding to conformational state-specific models of hERG channel structures embedded in hydrated lipid bilayers. MD simulation-derived drug binding affinities as well as their association and dissociation (“on” and “off”) rates were used as functional kinetic model parameters of hERG channel – drug interactions and subsequently used in cardiac cell and tissue simulations to predict emergent drug effects on heart rhythm. This pipeline was successfully used to predict different pro-arrhythmia proclivities of two potent hERG blockers, dofetilide and moxifloxacin. We also elucidated molecular basis of stereospecific arrhythmogenic risks of two enantiomers of beta-blocking anti-arrhythmic drug sotalol. We have been expanding this pipeline to predict how multi-target binding of hERG channel blockers may ameliorate or exaggerate their pro-arrhythmia risks and how sex hormone can modulate drug arrhythmogenicity via direct hERG channel interactions. We are also making this pipeline more robust and high-throughput using Site-Identification by Ligand Competitive Saturation (SILCS) docking and machine learning (ML) techniques. Our in-silico predictive multiscale pipeline will help efficient assessment of cardiac toxicity of diverse drug candidates from their chemical structures.

Multi-scale modeling assessment of drug-induced cardiotoxicity: From atomistic modeling to heart rhythm

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.