A multidisciplinary study, unveiling lipophilic drug block of hERG1

Abstract

The human-ether-a-go-go-related gene (hERG) potassium channels conducts the rapid delayed rectifier current in cardiomyocytes, crucial for timely repolarization of the cardiac action potential. hERG is of great medical and pharmaceutical concern as the channel is susceptible to block by structurally and therapeutically diverse drugs. The block comprformatomises hERG function in the action potential duration in ventricular cardiomyocytes, causing acquired long QT syndrome, hallmark of the deadly Torsade de Pointe. As such, deciphering molecular underpinnings and mechanisms of drug block is essential in understanding and preventing dangerous side effects of drugs and aids in the design of new and safer therapeutics. The exact mechanisms of drug block remained elusive as the structure of the channel was not available. It was however, commonly accepted that all drugs bind only directly to the central cavity, thereby plugging the normal flow of ions through the channel. This thesis elucidates the molecular underpinnings of a drug block, specifically we explore the lipophilic binding route and unique structure-function features of the channel by linking computational approaches with experimental mutagenesis and electrophysiology. We gain insight into conformational changes within hERG at the molecular level and firmly establish a presence of unique lipophilic route, making the channel susceptible to wide range of drugs. Our findings suggest the dynamic nature of the internal cavity and fine interplay between aromatic cassette in S5 and S6, (M651-F656-F557) determine the state dependant binding of drugs and availability of the lipophilic route or “fenestration windows”. For a long time, the lipophilic route of drug binding has been dismissed and overlooked until the availability of the new structure. Further, we demonstrate novel structural features in the hERG structure via the molecular dynamic simulations and electrophysiology, notably the presence of omega current and formation of salt bridges with wide water crevices in the VSD as predicted in plethora of biophysical experiments. Overall, the new knowledge resulting from my doctoral thesis provides insight into the fundamental properties of drug block of hERG and have clinical and pharmaceutical implications, helping the development of better therapeutics of the future and improving prediction of proarrhythmic propensity.