The Methanesulfonamide Group: Bright and Dark Sides of hERG Potassium Channel Inhibition

Our review focuses on methanesulfonamide-containing compounds, a well-characterized class of high-affinity blockers of the hERG potassium channel, which plays a critical role in cardiac repolarization by mediating the cardiac I_Kr. These compounds, which include notable class III antiarrhythmic drugs such as dofetilide and d-sotalol, block the hERG channel in its open state by binding within the inner vestibule. This interaction is particularly strong with some residues and the compounds form hydrogen bonds with others. This binding results in high-affinity inhibition with slow dissociation kinetics, frequently leading to drug trapping and prolonged action potential duration (APD). This can predispose patients to arrhythmias, including Torsades de Pointes. Beyond cardiac drugs, there are several non-cardiac methanesulfonamide drugs that also block the hERG channel. This causes pro-arrhythmic side effects despite their primary indications. The clinical significance of these effects, especially in patients with impaired drug elimination, is that accumulation increases the risk of arrhythmia. The objective of forthcoming research endeavors is to mitigate hERG affinity, with the aim of reducing pro-arrhythmic risks while maintaining therapeutic efficacy. This means structural modifications that seek to remove or modify the methanesulfonamide group. Machine learning also emerged as promising tool for exploring drug-protein interactions. It is evident that the methanesulfonamide moiety plays a pivotal role in the structural basis of hERG blockade. However, it should be noted that this moiety does not necessarily represent a universal pharmacophore. This observation underscores the necessity for a nuanced approach in drug development, aimed at achieving a balance between efficacy and safety.