Insights into the Molecular Mechanism of hERG1 Channel Activation and Blockade by Drugs

Durdağı, Serdar; Subbotina, Julia O.; Lees‐Miller, James P.; Guo, Jiqing; Duff, Henry J.; Noskov, Sergei Y.

doi:10.2174/092986710792927886

Cited by 53 publications

(49 citation statements)

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“…As in all in silico docking approaches, the chosen strategy has limitations. Previous theoretical studies (Mobley and Dill, 2009;Durdagi et al, 2010) on the membrane protein-drug interactions with free energy and molecular dynamics simulations highlighted an importance of correct accounting for the conformational dynamics of the substrate in the bulk phase and the receptor site. Despite the limitations of the molecular docking scores, it may provide insights into potential binding pockets.…”

Section: Resultsmentioning

confidence: 99%

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Durdağı¹,

Guo²,

Lees‐Miller³

et al. 2012

J Pharmacol Exp Ther

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Loss-of -function mutations in human ether-a-go-go-related gene 1 (hERG1) is associated with life-threatening arrhythmias. hERG1 activators are being developed as treatments for acquired or genetic forms of long QT syndrome. The locations of the putative binding pockets for activators are still being elucidated. In silico docking of the activator 1,3-bis-(2-hydroxy-5-trifluoromethylphenyl)-urea (NS1643) to an S1-S6 transmembrane homology model of hERG1 predicted putative binding sites. The predictions of the in silico docking guided subsequent in vitro mutagenesis and electrophysiological measurements. The novel interacting site for NS1643 is predicted around Asn629 at the outer mouth of the channel. The applied N629H mutation is the sole amino acid replacement in the literature that abrogates the NS1643-induced left shift of the V 1/2 of activation. In contrast, both N629T and N629D showed pharmacologic responses similar to wild type. Another important interacting pocket is predicted at the intracellular surface in the S4 -S5 linker. Mutagenesis of the residues critical to interactions in this pocket had major effects on the pharmacologic response to NS1643. The inward conductance elicited by hyperpolarization of D540K hERG1 was abrogated by NS1643 treatment, suggesting that it alters the inward movement of the S4 segment. The neighboring E544L mutation markedly exaggerated tail-current responses to NS1643. However, an L564A substitution inhibited drug response. Structure-guided mutagenesis identified widespread clusters of amino acids modulating drug-induced shifts in inactivation; such modulation may reflect allosteric changes in tertiary structure. Modelguided mutagenesis led to the discovery of a range of novel interacting residues that modify NS1643-induced pharmacologic responses.

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Section: Resultsmentioning

confidence: 99%

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Durdağı¹,

Guo²,

Lees‐Miller³

et al. 2012

J Pharmacol Exp Ther

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“…Several manuscripts have been published that included an excellent summary of computational methods for predicting hERG inhibition [12][13][14][15][16][17][18]. Here we summarize and group the representative models by the methods they used and briefly describe how these models predict hERG binding affinity and the potential interactions between hERG inhibitors and the channel.…”

Section: Future Science Groupmentioning

confidence: 99%

In Silico Prediction of hERG Inhibition

et al. 2015

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The voltage-gated potassium channel encoded by hERG carries a delayed rectifying potassium current (IKr) underlying repolarization of the cardiac action potential. Pharmacological blockade of the hERG channel results in slowed repolarization and therefore prolongation of action potential duration and an increase in the QT interval as measured on an electrocardiogram. Those are possible to cause sudden death, leading to the withdrawals of many drugs, which is the reason for hERG screening. Computational in silico prediction models provide a rapid, economic way to screen compounds during early drug discovery. In this review, hERG prediction models are classified as 2D and 3D quantitative structure-activity relationship models, pharmacophore models, classification models, and structure based models (using homology models of hERG).

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“…Additionally, the inhibition of hERG (human ether-ago-go-related gene) potassium ion (K ? ) channel [53] and the central nervous system (CNS) activity [54] have been evaluated to account for the effect on toxicity of the saquinavir-based fullerene derivatives 8-23. QikProp uses experimental results of 710 compounds, including about 500 drugs and related heterocycles.…”

Section: Admet Calculationsmentioning

confidence: 99%

Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson–Boltzmann surface area calculations

Tzoupis

Leonis

Durdağı

et al. 2011

J Comput Aided Mol Des

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The objectives of this study include the design of a series of novel fullerene-based inhibitors for HIV-1 protease (HIV-1 PR), by employing two strategies that can also be applied to the design of inhibitors for any other target. Additionally, the interactions which contribute to the observed exceptionally high binding free energies were analyzed. In particular, we investigated: (1) hydrogen bonding (H-bond) interactions between specific fullerene derivatives and the protease, (2) the regions of HIV-1 PR that play a significant role in binding, (3) protease changes upon binding and (4) various contributions to the binding free energy, in order to identify the most significant of them. This study has been performed by employing a docking technique, two 3D-QSAR models, molecular dynamics (MD) simulations and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. Our computed binding free energies are in satisfactory agreement with the experimental results. The suitability of specific fullerene derivatives as drug candidates was further enhanced, after ADMET (absorption, distribution, metabolism, excretion and toxicity) properties have been estimated to be promising. The outcomes of this study revealed important protein-ligand interaction patterns that may lead towards the development of novel, potent HIV-1 PR inhibitors.

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Insights into the Molecular Mechanism of hERG1 Channel Activation and Blockade by Drugs

Cited by 53 publications

References 0 publications

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

In Silico Prediction of hERG Inhibition

Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson–Boltzmann surface area calculations

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