Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking

Zhang, Y.H.; Colenso, Charlie K; Harchi, Aziza El; Cheng, Hongwei; Witchel, Harry J.; Dempsey, Christopher E.; Hancox, Jules C.

doi:10.1016/j.bcp.2016.05.013

Cited by 42 publications

(79 citation statements)

References 56 publications

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“…Similarly, hERG block induced by dronedarone and fluvoxamine was only weakly sensitivity to Y652A and F656A mutations. But in the case of amiodarone drug, its hERG blocking activity was significantly affected by Y652A mutation, but not by F656A. This clearly indicates that, although the hERG blockers bind to the same binding site at the inner cavity, their binding modes could be significantly different from each other.…”

Section: Herg Channel: Structural Topologymentioning

confidence: 96%

Development of Safe Drugs: The hERG Challenge

Kalyaanamoorthy

Barakat

2017

Medicinal Research Reviews

119

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Drug-induced blockade of human ether-a-go-go-related gene (hERG) remains a major impediment in delivering safe drugs to the market. Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off-target interactions with hERG. Thus, identifying the potential hERG blockers at early stages of lead discovery is fast evolving as a standard in drug design and development. A number of in silico structure-based models of hERG have been developed as a low-cost solution to evaluate drugs for hERG liability, and it is now agreed that the hERG blockers bind at the large central cavity of the channel. Nevertheless, there is no clear convergence on the appropriate drug binding modes against the channel. The proposed binding modes differ in their orientations and interpretations on the role of key residues in the channel. Such ambiguities in the modes of binding remain to be a significant challenge in achieving efficient computational predictive models and in saving many important already Food and Drug Administration approved drugs. In this review, we discuss the spectrum of reported binding modes for hERG blockers, the various in silico models developed for predicting a drug's affinity to hERG, and the known successful optimization strategies to avoid off-target interactions with hERG.

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Section: Herg Channel: Structural Topologymentioning

confidence: 96%

Development of Safe Drugs: The hERG Challenge

Kalyaanamoorthy

Barakat

2017

Medicinal Research Reviews

119

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“…This can explain why blocking compounds that are unaffected by experimental removal of channel inactivation are either small (perhexiline), bulky (erythromycin) or possess unusual chemical moieties (quinidine) and may not interact with 660–667 residues or interact in totally different ways. MD simulations were reported with the potent blocker amiodarone in the hERG cavity, with the halogenated ring surrounded by Phe656 residues and placing the benzofuranyl‐butyl moiety in close contact with the lower residues . That binding mode is in full agreement with the new binding mode, but may also be regarded to slightly resemble the “classical” one, due to the presence of an aliphatic tail in the lower part of the cavity.…”

Section: Resultsmentioning

confidence: 54%

“…It is thought that gating of hERG supposes conformational changes of the lower part of S6 helices, which may include a twisting of the whole helices and a positional change of the aromatic residues in the hERG cavity, placing them in an much more favorable position to interact with blockers . Similarly to clofilium and ibutilide, channel blocking by other potent blockers like MK‐499 (IC 50 =34 nM) and amiodarone (IC 50 =45 nM) was significantly reduced by V659A but also, to a lower extent, by mutating residues placed lower on S6. However, channel blocking by moderate‐affinity compounds like vesnarinone (IC 50 =1060 nM), cisapride (IC 50 =650 nM), terfenadine (IC 50 =350 nM), dofetilide (IC 50 =420 nM) and E‐4031 (IC 50 =570 nM) was inhibited by V659A mutation to different extents, but not by any mutation of residues located lower on the S6.…”

Section: Resultsmentioning

confidence: 99%

“…Since the intracellular activation gate is formed at Gln664, it can be assumed that important conformational changes of the 660–667 helix occur due to channel kinetics . High‐affinity blockade was attenuated even by some conservative mutations in the 660–667 region (I663A, L666A), which implies, if they shall not influence channel gating, that interactions may exist between those residues and the blockers ,,. Therefore, a strong but distant contact between the high‐affinity blockers and 660–667 residues could take place, one that can finely modify the overall architecture of that specific region located under the inner cavity of hERG.…”

Section: Resultsmentioning

confidence: 99%

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Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium

Șterbuleac

Maniu

2018

Molecular Informatics

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The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations. The results show an unexpected binding mode, in which the quaternary nitrogen is placed in the upper part of the inner cavity, interacting strongly with Ser624, while the chlorophenyl group is located in the lower part, in better agreement with previous experimental results. This novel binding position also explains the higher affinity of clofilium for the related hEag1 channel and was correlated with the possibility that potent hERG blockers interact in specific ways with the residues near the intracellular activation gate, offering a new explanation that could help predict the potency of other hERG-blocking compounds.

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“…Due to the known low expression and altered kinetic properties of some hERG mutants (in particular T623A and F656A clones), we measured the inward current of the T623A and F656A mutants in high (94 mM) external K + solution, since the external K + concentration increase is aimed to maximize the inward tail currents [25, 26, 30]. Consequently, we tested lubeluzole block of wild-type I hERG under similar experimental conditions, to examine whether a change in the ionic conditions affects hERG affinity toward lubeluzole.…”

Section: Resultsmentioning

confidence: 99%

Molecular Insights into hERG Potassium Channel Blockade by Lubeluzole

Gualdani

Cavalluzzi

Tadini‐Buoninsegni

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in preclinical models of ischemic stroke. However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. Since the cardiac cellular effects of lubeluzole have not been described thus far, an explanation for the lubeluzole-induced QT interval prolongation is lacking. Methods: We tested the affinity of lubeluzole, its enantiomer, and the racemate for hERG channel using the patch-clamp technique. We synthesized and tested two simplified model compounds corresponding to two moieties included in the lubeluzole structure. The obtained experimental results were rationalized by docking simulation on the recently reported cryo-electron microscopy (cryo-EM) structure of hERG. Group efficiency analysis was performed in order to individuate the fragment most contributing to binding. Results: We found that lubeluzole and its R enantiomer are highly potent inhibitors of human ether-ago-go-related gene (hERG) channel with an IC₅₀ value of 12.9 ± 0.7 nM and 11.3 ± 0.8 nM, respectively. In the presence of lubeluzole, steady-state activation and inactivation of hERG channel were shifted to more negative potentials and inactivation kinetics was accelerated. Mutations of aromatic residues (Y652A and F656A) in the channel inner cavity significantly reduced the inhibitory effect of lubeluzole. Molecular docking simulations performed on the near atomic resolution cryo-electron microscopy structures of hERG supported the role of Y652 and F656 as the main contributors to high affinity binding. Group efficiency analysis indicated that both 1,3-benzothiazol-2-amine and 3-aryloxy-2-propanolamine moieties contribute to drug binding with the former giving higher contribution. Conclusions: This study suggests the possibility to modulate lubeluzole hERG blockade by introducing suitable substituents onto one or both constituting portions of the parent compound in order to either reduce potency (i. e. torsadogenic potential) or potentiate affinity (useful for class III antiarrhythmic and anticancer agent development).

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Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking

Abstract: Graphical abstract

Cited by 42 publications

References 56 publications

Development of Safe Drugs: The hERG Challenge

Development of Safe Drugs: The hERG Challenge

Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium

Molecular Insights into hERG Potassium Channel Blockade by Lubeluzole

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