UC Davis

Cardiotoxicity risks in the form cardiac arrhythmias prevent new drug candidates to advance from pre-clinical development. One measure of this risk is the prolongation of the QT interval on the electrocardiogram (ECG) - a surrogate marker for abnormal electrical activity and a potential precursor for fatal ventricular arrhythmias. A number of high-profile drug failures due to their cardiotoxicity have been attributed to drug interactions with the voltage-gated potassium channel Kv11.1, also known as the human Ether-a-go-go Related Gene Encoded Protein (or “hERG”), a cardiac ion transport protein largely responsible for the repolarization of the cardiac action potential and thus QT interval duration. Drugs from multiple classes block hERG channel and can cause QT interval prolongation and possibly arrhythmias. In this work we will focus on beta-blockers, which are used to treat cardiovascular disorders including some arrhythmias but inadvertently can be arrhythmogenic as well. One such drug molecule is d-sotalol, the dextrorotary stereoisomer of the beta-blocking anti-arrhythmic drug dl-sotalol, which proved to induce fatal arrhythmias due to hERG blockade in the “Survival with Oral D-Sotalol” clinical study. Sotalol is otherwise is formulated as a racemic beta blocker indicated for the treatment of arrhythmias like atrial fibrillation by blocking the activation of beta-adrenergic receptors, a target blocked only by the l-stereoisomer. Yet l-sotalol is as effective at blocking hERG as its dextrorotary counterpart. It seems that beta-blocking activity may attenuate arrhythmogenic risks posed by sotalol-induced QT prolongation, and experimental evidence supports this conclusion. However, the molecular mechanism that governs this selectivity on the beta-adrenergic receptor remains unknown. Here we examine stereospecific interactions of the stereoisomers of sotalol with the beta-adrenergic receptor subtypes β1 and β2, but not before examining hERG conduction and the nature of hERG channel blockade by sotalol. In pursuing this line of inquiry, we find that the while molecular dynamics simulations can support experimental evidence regarding hERG-blockade, assessing beta-blockade in the orthosteric ligand binding pocket of the beta-receptors using molecular docking approach, as opposed to molecular dynamics, falls short of recapitulating this physiological phenomenon.