Computer Simulations of Structure–Activity Relationships for hERG Channel Blockers

Abstract

T he recent progress in the determination of three-dimensional (3D) structures of biological ion channels holds great promise for obtaining a structure-based quantitative view of interactions between channels and ligands of biological and pharmacological importance. Notwithstanding the increasing number of ion channel structures that have been determined, 1À6 there are, however, still relatively few complexes with ligands, such as channel blockers, that have been described. 7,8 From a pharmaceutical viewpoint, several of the most relevant channels have also not been structurally characterized at the atomic level. In the K + channel field, a number of key structures have been obtained 1À6 that in some cases allow for relatively reliable homology modeling of related channels and their interactions with ligands. 1,3,5 Of particular interest among the human K + channels is the human ether-a-go-go-related gene (hERG) channel that is associated with both inherited and drug-induced long QT syndrome. 9,10 The latter problem, which is a side effect caused by blockade of hERG by various compounds, is a major obstacle for drug development and is presently receiving intense attention. 11 In the cardiac action potential, the hERG channel carries the rapid delayed rectifier (I Kr ) current, and its blockade leads to a prolongation of the QT interval, with severe risks for arrhythmias and sudden death. 12,13 Most compounds causing such blockade apparently become trapped in the relatively unspecific internal pore cavity of the channel, and it is therefore of major interest to investigate the binding properties of this cavity. Unfortunately, the pore-forming helices of hERG show only relatively weak homology to K + channels with known 3D structure and particularly with members of the Shaker-related family. 5,14 The short pore helix, the selectivity filter, and the innermost S6 helices lining the pore can, however, be confidently aligned on the basis of conservation of the filter region and a glycine hinge in S6. 15,16 The situation is more ambiguous for the S5 helices that pack against the S6 helices in the tetrameric structure, and several alignments of S5 against K + channels of known structure have been published. 15À18 We have recently reported an analysis of seven different alignments and 3D pore models utilizing conventional 3D structure quality validation methods as well as molecular dynamics (MD) simulations. From that work, one model (model 6 of ref 19) emerged as the most consistent, and it also provided a rationalization of the results from mutation scanning experiments. 20 Here, we investigate the performance of our best hERG pore model with respect to prediction of binding affinities for a series of sertindole analogues listed in Table 1. 21 Sertindole is an indolylpiperidine antipsychotic agent that has nanomolar affinities for dopamine D 2 , serotonin 5-HT 2 , and R 1 adrenergic ABSTRACT: The hERG potassium channel is of major pharmaceutical importance, and its blockade by various compounds, potentially causin...

hERG K+Channels: Structure, Function, and Clinical Significance

“…Second, all studies highlighted the importance of multiple -stacking and hydrophobic interactions with the aromatic side chains of two S6 helix residues, Tyr652 and Phe656. Furthermore, the simulations suggest that drugs can form aromatic and hydrophobic interactions with more than one subunit of the channel (74,168,282,399,591,705). This fits well with ligand-derived models which indicate that multiple aromatic and/or aliphatic chains are critical for high-affinity block (156,523,569,617,627,638).…”

“…A further complication is the inclusion of lipid membranes into these models using molecular dynamics simulations, which may be important for a stable Kv11.1 channel model (399,595). Despite these significant problems in obtaining an accurate receptor model of Kv11.1, several sophisticated in silico models of drug binding exist (74,160,168,282,399,591,595,705). The different docking strategies and diverse test structures used in these studies makes a comparison of binding conformations difficult.…”

A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity

“…Most of the previously available hERG computational models are ligand-based but since these rely mainly on the existence of structural similarities between the tested drug candidate and previously reported known hERG blockers, these models have limited value in the frequent case of a novel drug structure (Aronov and Goldman, 2004;Coi et al, 2006;Du-Cuny et al, 2011;Ekins et al, 2002;Keseru, 2003;Song and Clark, 2006;Su et al, 2010;Yoshida and Niwa, 2006). Producing a reliable hERG ion channel structure-based model to directly test drug binding (Broccatelli et al, 2012;Du-Cuny et al, 2011) has therefore been of high priority but in the absence of a hERG crystal structure, this has been limited to creating homology models that have excluded a large portion of the hERG channel and which display very limited conformational flexibility (Boukharta et al, 2011;Di Martino et al, 2013;Farid et al, 2006;Osterberg and Aqvist, 2005).…”

“…Most previous models have also neglected solvent and ions' effects on interactions between the hERG channel and the bound ligand. Furthermore, only specific classes of compounds were analyzed with restraints imposed on atoms far from the binding region (Boukharta et al, 2011). Our computational structural model reported here remedies all of these previous deficiencies and identifies binding modes for hERG blockers and quantifies their hERG-blockade activity.…”

A study of the structural properties and thermal stability of human Bcl-2 by molecular dynamics simulations

“…Thus, conformational movements induced by high temperatures suggest that to avoid interactions of Bcl-2 with pro-apoptotic proteins, the FLD hides the core of the protein. However, there is no experimental evidence of this observation (Boukharta et al, 2011). Another reported functional role of the FLD is its participation in regulating cell survival by interaction with p53, a key cell cycle arrest protein activated in response to DNA damage (Deng et al, 2006).…”