hERG Potassium Channels and the Structural Basis of Drug-Induced Arrhythmias

Abstract

hERG potassium channels have a critical role in the normal electrical activity of the heart. The block of hERG channels can cause the drug-induced form of long QT syndrome, a cardiac disorder that carries an increased risk of cardiac arrhythmias and sudden death. hERG channels are extraordinarily sensitive to block by large numbers of structurally diverse drugs. In previous years, the risk of compounds causing this cardiotoxic side effect has been a common reason for the failure of compounds in preclinical safety trials. Pharmaceutical companies have successfully utilized and developed higher throughput techniques for the early detection of compounds that block hERG, and this has helped reduce the number of compounds that fail in the late stages of development. Nevertheless, this screening-based approach is expensive, consumes chemistry resources, and bypasses the problem rather than shedding light on it. Crystal structures of potassium channels have facilitated studies into the structural basis for the gating and block of hERG channels. Most drugs bind within the inner cavity, and the individual amino acids that form the drug binding site have been identified by site-directed mutagenesis approaches. Gating processes have an important influence on the drug-binding site. Recent advances in our understanding of channel activation and inactivation are providing insight into why hERG channels are more susceptible to block than other K + channels. Knowledge of the structure of the drug-binding site and precise nature of interactions with drug molecules should assist efforts to develop drugs without the propensity to cause cardiac arrhythmias.

Non-invasive Video Image-based Analysis Method Coupled to Field Potential Recording for Evaluation of the Drug-induced Effect in Cardiac Tissue

“…4 However, measuring only one type of current for screening drug-induced effects for a range of channels is expected to give faulty results. An in vitro cardiac safety assay that can integrate more than only the hERG ion channel current is, therefore, a great concern of the pharmaceutical industry to achieve a better drug regulatory program.…”

In silico Analysis on hERG Channel Blocking Effect of a Series of T-type Calcium Channel Blockers

“…4 Now, testing the hERG blockade is a routine process at an early stage of drug development before clinical testing. 5 For these reasons, several attempts have been made to find out the binding mechanism of the hERG blockers. Above all, many studies have discovered the hERG channel structure, which has helped researchers understand about drug binding.…”

“…Ala-scanning mutagenesis studies have identified critical residues interacting with drugs on those transmembranes. 5 Those are two aromatic residues and two polar residues : Tyr 652 and Phe 656 on S6 and Thr 623 and Ser 624 on the pore helix. 5 Some residues are also known as interacting with hERG blockers by the indirect method through an allosteric effect.…”

“…5 Those are two aromatic residues and two polar residues : Tyr 652 and Phe 656 on S6 and Thr 623 and Ser 624 on the pore helix. 5 Some residues are also known as interacting with hERG blockers by the indirect method through an allosteric effect. 5 On the other hand, it was also found that the dimension of the pore also changed according to its conformational alteration : open state and closed state.…”

“…5 Some residues are also known as interacting with hERG blockers by the indirect method through an allosteric effect. 5 On the other hand, it was also found that the dimension of the pore also changed according to its conformational alteration : open state and closed state. 1 The electrophysiology experiments revealed that the channel must be open state for drugs to bind.…”