Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon.

Saba Munawar,Ishrat Jabeen,Jamie I Vandenberg

doi:10.3390/ijms20143385

Abstract

Human ether a-go-go related gene (hERG) or KV11.1 potassium channels mediate the rapid delayed rectifier current (IKr) in cardiac myocytes. Drug-induced inhibition of hERG channels has been implicated in the development of acquired long QT syndrome type (aLQTS) and fatal arrhythmias. Several marketed drugs have been withdrawn for this reason. Therefore, there is considerable interest in developing better tests for predicting drugs which can block the hERG channel. The drug-binding pocket in hERG channels, which lies below the selectivity filter, normally contains K+ ions and water molecules. In this study, we test the hypothesis that these water molecules impact drug binding to hERG. We developed 3D QSAR models based on alignment independent descriptors (GRIND) using docked ligands in open and closed conformations of hERG in the presence (solvated) and absence (non-solvated) of water molecules. The ligand–protein interaction fingerprints (PLIF) scheme was used to summarize and compare the interactions. All models delineated similar 3D hERG binding features, however, small deviations of about ~0.4 Å were observed between important hotspots of molecular interaction fields (MIFs) between solvated and non-solvated hERG models. These small changes in conformations do not affect the performance and predictive power of the model to any significant extent. The model that exhibits the best statistical values was attained with a cryo_EM structure of the hERG channel in open state without water. This model also showed the best R2 of 0.58 and 0.51 for the internal and external validation test sets respectively. Our results suggest that the inclusion of water molecules during the docking process has little effect on conformations and this conformational change does not impact the predictive ability of the 3D QSAR models.

Highlights

Over the last two decades, a vast array of structurally and functionally unrelated drugs including antiarrhythmics [1], antibiotics [2,3], antipsychotics [3] and antihistamines [4] have been withdrawn from the market due to their association with prolongation of the ventricular action potential that causes acquired long QT syndrome [5]
The acquired long QT syndrome (aLQTs) is characterized by QT interval prolongation on the surface of an electrocardiogram (ECG) that may lead to fatal ventricular arrhythmias, that is, Torsade de Pointes (TdPs) [6]
Our results suggest that the presence of water molecules in the central cavity of human ether-a-go-go-related gene (hERG) channel www.mdpi.com/journal/ijms is involved in water-mediated ligand–protein interactions

Summary

Introduction

Over the last two decades, a vast array of structurally and functionally unrelated drugs including antiarrhythmics (dofetilide) [1], antibiotics (grepafloxacin) [2,3], antipsychotics (sertindole, haloperidol) [3] and antihistamines (astemizole) [4] have been withdrawn from the market due to their association with prolongation of the ventricular action potential that causes acquired long QT syndrome (aLQTs) [5]. The major cause of drug-induced QT interval prolongation is the trapping of drugs in the pore of the human ether-a-go-go-related gene (hERG) or KV11.1 potassium ion channel [7]. It has been estimated that 60% of the drugs in the development phase show hERG liability [8], 15% of drugs on the market was associated with a tendency to prolong QT interval and 4% was associated with TdPs (www.crediblemeds.org). To assess the pro-arrhythmic risk of new chemical entities (NCEs), the regularity authorities stipulate pre-clinical safety guidelines that all drugs must be tested for their hERG liability and tendency to induce QT interval prolongation [9,10]. The International Conference on Harmonisation (ICH) has recommended a thorough QT/QTcalculated study for any bioavailable drug before marketing [11]

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