Modeling hERG and its Interactions with Drugs: Recent Advances in Light of Current Potassium Channel Simulations

Recanatini, Maurizio; Cavalli, Andrea; Masetti, Matteo

doi:10.1002/cmdc.200700264

Cited by 51 publications

(41 citation statements)

References 78 publications

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“…Most previous molecular simulations of K + channels appear to be inconsistent with this feature of the knock-on model as they show stable states with both double and triple occupancy of the selectivity filter. 6 In addition, the knock-on model predicts [Eqs. (3) and (4)] that permeation through an ion channel between symmetric solutions will be directly proportional to the permeant ion concentration and that the current-voltage curves will generally be superlinear (i.e., conduction will be super-Ohmic as shown in Fig.…”

Section: 31mentioning

confidence: 99%

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A permeation theory for single-file ion channels: One- and two-step models

Nelson

2011

The Journal of Chemical Physics

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How many steps are required to model permeation through ion channels? This question is investigated by comparing one-and two-step models of permeation with experiment and MD simulation for the first time. In recent MD simulations, the observed permeation mechanism was identified as resembling a Hodgkin and Keynes knock-on mechanism with one voltage-dependent rate-determining step [Jensen et al., PNAS 107, 5833 (2010)]. These previously published simulation data are fitted to a one-step knock-on model that successfully explains the highly non-Ohmic current-voltage curve observed in the simulation. However, these predictions (and the simulations upon which they are based) are not representative of real channel behavior, which is typically Ohmic at low voltages. A two-step association/dissociation (A/D) model is then compared with experiment for the first time. This two-parameter model is shown to be remarkably consistent with previously published permeation experiments through the MaxiK potassium channel over a wide range of concentrations and positive voltages. The A/D model also provides a first-order explanation of permeation through the Shaker potassium channel, but it does not explain the asymmetry observed experimentally. To address this, a new asymmetric variant of the A/D model is developed using the present theoretical framework. It includes a third parameter that represents the value of the "permeation coordinate" (fractional electric potential energy) corresponding to the triply occupied state n of the channel. This asymmetric A/D model is fitted to published permeation data through the Shaker potassium channel at physiological concentrations, and it successfully predicts qualitative changes in the negative current-voltage data (including a transition to super-Ohmic behavior) based solely on a fit to positive-voltage data (that appear linear). The A/D model appears to be qualitatively consistent with a large group of published MD simulations, but no quantitative comparison has yet been made. The A/D model makes a network of predictions for how the elementary steps and the channel occupancy vary with both concentration and voltage. In addition, the proposed theoretical framework suggests a new way of plotting the energetics of the simulated system using a one-dimensional permeation coordinate that uses electric potential energy as a metric for the net fractional progress through the permeation mechanism. This approach has the potential to provide a quantitative connection between atomistic simulations and permeation experiments for the first time.

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Section: 31mentioning

confidence: 99%

“…This concertedassociation/dissociation hypothesis allowed for the possibility that permeation might proceed according to just two steps. 5 This two-step hypothesis is now supported by a large group of simulations, [6][7][8][9][10][11][12][13][14][15] but no comparison of this two-step model with experiment has yet been conducted.…”

Section: Introductionmentioning

confidence: 99%

A permeation theory for single-file ion channels: One- and two-step models

Nelson

2011

The Journal of Chemical Physics

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“…This makes it diffi cult to recognize common properties of the compounds that block the channel. The ligand-based approach has been adopted to extract the features of hERG blockers in terms of inhibition of hERG current [9][10][11][12][13]. These methods include traditional two-dimensional (2D)-quantitative structure activity relationships (QSAR) [11,[14][15][16], 3D-QSAR [17][18][19][20][21][22], and classifi cation [23][24][25][26] methods.…”

Section: Ligand-based Prediction System For the Blockade Of Herg Currentmentioning

confidence: 99%

“…Next we introduce the structure-based estimation of ion conduction of hERG in complex with compounds with sequential computational approaches. [3,9,12,13]. To simulate the association of compound and hERG with a protein-based approach, a 3D structure of hERG is required.…”

Section: In Silico Prediction Systems For Chemical Block Of Hergmentioning

confidence: 99%

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

et al. 2008

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A variety of compounds with different chemical properties directly interact with the cardiac repolarizing K + channel encoded by the human ether-a-go-go-related gene (hERG). This causes acquired forms of QT prolongation, which can result in lethal cardiac arrhythmias, including torsades de pointes one of the most serious adverse effects of various therapeutic agents. Prediction of this phenomenon will improve the safety of pharmacological therapy and also facilitate the process of drug development. Here we propose a strategy for the development of an in silico system to predict the potency of chemical compounds to block hERG. The system consists of two sequential processes. The first process is a ligand-based prediction to estimate half-maximal concentrations for the block of compounds inhibiting hERG current using the relationship between chemical features and activities of compounds. The second process is a protein-based prediction that comprises homology modeling of hERG, docking simulation of chemical-channel interaction, analysis of the shape of the channel pore cavity, and Brownian dynamics simulation to estimate hERG currents in the presence and absence of chemical blockers. Since each process is a combination of various calculations, the criterion for assessment at each calculation and the strategy to integrate these steps are significant for the construction of the system to predict a chemical's block of hERG current and also to predict the risk of inducing cardiac arrhythmias from the chemical information. The principles and criteria of elemental computations along this strategy are described.Key words: hERG, quantitative structure-activity relationship, molecular docking, Brownian dynamics simulation.Many ion channels and ion transporting systems contribute to the generation of the action potential of the heart. The ventricular action potential possesses a longlasting plateau that is terminated by the activation of repolarizing K + currents, I Kr and I Ks . The disturbance of these currents causes prolongation of the action potential duration and thus the QT interval of the electrocardiogram, and in many cases a worsening of transmural dispersion of repolarization [1][2][3]. These are the substrates for generation of life-threatening cardiac arrhythmias, including torsades de pointes. Many compounds inhibit I Kr , whose pore-forming subunit is the human ether-a-gogo-related gene (hERG) product. This can cause acquired forms of long QT syndrome [4][5][6]. The compounds exhibit a broad spectrum, including not only cardiac ion channel blockers, but also antipsychotic agents, antidepressant agents, antimicrobial agents, phosphodiesterase inhibitors, topoisomerase II inhibitors, and antagonists for G protein-coupled receptors, such as nonsedating antihistamine H 1 receptor blockers and β blockers [6]. The development of methods that could predict this phenomenon would improve the safety of pharmacological therapy and also facilitate the process of drug development.Here we propose an in silico str...

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“…1B; for reviews, see Sanguinetti and Mitcheson, 2005;Sanguinetti and Tristani-Firouzi, 2006). Progressively more detailed knowledge of drug-binding mechanisms from structure-function analysis (Sanguinetti and Mitcheson, 2005;Sanguinetti and Tristani-Firouzi, 2006) and from in silico modeling of hERG-drug interactions (Recanatini et al, 2008) may ultimately facilitate removal of potential hERG blockade early during the drug design process. Cisapride has figured repeatedly in structure-function analyses of hERG channel inhibition (Mitcheson et al, 2000a;Chen et al, 2002;Fernandez et al, 2004).…”

mentioning

confidence: 99%

Refining Insights into High-Affinity Drug Binding to the Human Ether-à-go-go-Related Gene Potassium Channel

Hancox¹,

James²

2008

Molecular Pharmacology

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hERG (human ether-à -go-go-related gene) potassium (K ϩ ) channels play a crucial role in electrophysiological activity in the heart, exerting a profound influence on ventricular action potential repolarization and on the duration of the QT interval of the electrocardiogram. hERG channels are strongly implicated in the acquired form of long QT syndrome in that they exhibit a unique susceptibility to pharmacological inhibition by therapeutically and chemically diverse drugs. Investigations over a number of years provide compelling evidence that a comparatively large inner cavity and the presence of particular aromatic amino acid residues (Tyr652 and Phe656) on the inner (S6) helices of the channel are important features that allow hERG to accommodate and bind disparate drugs. However, whereas functional hERG channels are composed of four identical subunits, blocking molecules may not interact equally with aromatic residues from each of the four subunits. In this issue of Molecular Pharmacology, Myokai et al. (p. 1643) report for the first time the use of tandem dimers incorporating mutations to Tyr652 and Phe656 to elucidate asymmetric binding of the high affinity hERG inhibitor cisapride. Not only has this approach provided increased information on spatial arrangements involved in cisapride binding to the channel, but it offers a powerful means of refining the wider understanding of hERG channel structurefunction in relation to drug binding.

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Modeling hERG and its Interactions with Drugs: Recent Advances in Light of Current Potassium Channel Simulations

Cited by 51 publications

References 78 publications

A permeation theory for single-file ion channels: One- and two-step models

A permeation theory for single-file ion channels: One- and two-step models

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

Refining Insights into High-Affinity Drug Binding to the Human Ether-à-go-go-Related Gene Potassium Channel

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