Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities.

Saba Munawar,Adam P Hill,Jamie I Vandenberg,Edwin G Tse,Matthew H Todd,Monique J Windley,Ishrat Jabeen

doi:10.3389/fphar.2018.01035

Abstract

The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50) prediction of identified hits. Finally selected two hits were experimentally evaluated for hERG inhibition potential (pIC50) using whole cell patch clamp assay. Overall, our results demonstrate a difference of less than ±1.6 log unit between experimentally determined and predicted hERG inhibition potential (IC50) of the selected hits. This revealed predictive ability and robustness of our models and could help in correctly rank the potency order (lower μM to higher nM range) against hERG.

Highlights

IntroductionA prolongation of the cardiac action potential and the QT interval on the surface electrocardiogram (ECG) has been associated with loss of function mutations in human ether-a-go-go-related gene (hERG) (Yang et al, 2009; Sun et al, 2013; Zhang et al, 2013) or drug-trapping inside the central cavity of the hERG potassium channel and may predispose to life-threatening ventricular tachyarrhythmia “Torsade-de-points” (TdP) (Roden, 2004; De Bruin et al, 2005)
The human ether-a-go-go-related gene encoded potassium ion (K+) channel is an important component of the pore-forming α-subunits that conduct the rapidly activated delayed rectifier potassium current (IKr) which is a major repolarization current of the cardiac action potential (Sanguinetti et al, 1995; Vandenberg et al, 2012)
Compounds tested by whole cell patch clamp experiment using both HEK293 and Chinese Hamster Ovary (CHO) cell lines were kept in the final data set of 207 human ether-a-go-go-related gene (hERG) inhibitors

Summary

Introduction

A prolongation of the cardiac action potential and the QT interval on the surface electrocardiogram (ECG) has been associated with loss of function mutations in hERG (Yang et al, 2009; Sun et al, 2013; Zhang et al, 2013) or drug-trapping inside the central cavity of the hERG potassium channel and may predispose to life-threatening ventricular tachyarrhythmia “Torsade-de-points” (TdP) (Roden, 2004; De Bruin et al, 2005). Other factors such as, electrolyte imbalance, ischemia are reported (Sauer and Newton-Cheh, 2012). There is considerable interest in screening for hERG block amongst future drug candidates (Redfern et al, 2003; Guth, 2007; Raschi et al, 2008)

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