Computational Toxicology

Chapter 3Computational Approaches for Predicting hERG Activity

Vinicius M. Alves, Rodolpho C. Braga and Carolina Horta Andrade

LabMol – Laboratory for Molecular Modeling and Design, Faculty of Pharmacy, Federal University of Goias, Goiania, GO, Brazil

Chapter Menu

1. Introduction
2. Computational Approaches
3. Ligand-Based Approaches
4. Structure-Based Approaches
5. Applications to Predict hERG Blockage
6. Other Computational Approaches Related to hERG Liability
7. Final Remarks

3.1 Introduction

The human ether-à-go-go related gene (hERG) is a gene (kcnh2) that encodes for a protein named Kv11.1, the α subunit of potassium ion channels. The hERG channels are expressed in a variety of tissues, but its clinical significance is more understood in the heart. This voltage-gated channel contributes to the coordination of the heart beat by mediating the repolarization of the cardiac action potential [1]. The structure and function of the heart are commonly evaluated by performing electrocardiography. In this examination, the electrical activity of the heart is recorded, where the QT interval is the measure of the duration of ventricular depolarization and repolarization in an electrocardiogram [2].

Abnormalities in the structure of hERG caused by different mutations are associated with increase or decrease of the QT interval, both related to sudden death. Short QT syndrome is a very rare condition caused by mutation and it is not discussed in this chapter. The long QT syndrome, also termed Torsade ...