Towards a Structural View of Drug Binding to hERG K + Channels

Abstract

The human ether-a-go-go-related gene (hERG) K channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding.

Challenges and advances in atomistic simulations of potassium and sodium ion channel gating and permeation

“…They exhibit a very short non-helical S4-S5 linker and lack a domain-swapped architecture commonly seen in other VGCC structures, in which the S1-S4 VSD is adjacent to the neighbouring PD S5-S6, rather than its own subunit. Therefore, it is likely that those channels have a different gating mechanism, with interactions between VSD and adjacent intracellular helix-turn-helix extensions of S6, termed C-linkers (Toombes & Swartz, 2016), or the juxtaposed intracellular N-terminal tails (Vandenberg et al 2017), suggested to play an important role. In a recent experimental/MD analysis study, a rack-and-pinion type of coupling between voltage sensors and pore gates involving interactions between S4 and S5 helices was suggested to be a dominant activation process of such channels and an alternative mechanism for K V channels in the Shaker family (Fernández-Mariño et al 2018).…”

Binding modes of hERG blockers: an unsolved mystery in the drug design arena

“…For example, terfenadine, an antihistamine, blocked the hERG channel causing fatal arrhythmias and, therefore, was withdrawn from the markets worldwide [4]. The possible lethal aftermath of drug-induced hERG blockade has made significant impacts on screening strategies, drug development, regulation, and approval procedures [2,3,5]. Recently, FDA has proposed a Comprehensive in-vitro Proarrhythmia Assay initiative to adapt a modern standard for the accurate assessment of potential drug-induced TdP [6].…”

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

“…Even though the direct inhibition of the hERG channel is the best characterized mechanism by which drugs can inhibit cardiac repolarization, other inhibitory mechanisms include the I Kr interference with hERG‐protein intracellular trafficking or promoting the degradation of this protein and action on the autonomic nervous system or the sinoatrial node . Stereochemical modeling indicates several different mechanisms by which drugs can inhibit this ion conductance, some of which would trap the drug in the inactivated channel, thereby extending the dissociation of the drug from the protein well beyond the plasma exposure . This suggests that in cardiotoxicity studies the modulation of repolarization should be followed for a period well beyond the plasma exposure to pharmacologically effective concentrations.…”

“…27 Stereochemical modeling indicates several different mechanisms by which drugs can inhibit this ion conductance, some of which would trap the drug in the inactivated channel, thereby extending the dissociation of the drug from the protein well beyond the plasma exposure. 20 This suggests that in cardiotoxicity studies the modulation of repolarization should be followed for a period well beyond the plasma exposure to pharmacologically effective concentrations. Such a delay in returning to baseline values can be interpreted as a form of hysteresis, that is, a delay between PK and pharmacodynamic effects.…”