Interaction between an Amantadine Analogue and the Transmembrane Portion of the Influenza A M2 Protein in Liposomes Probed by<sup>1</sup>H NMR Spectroscopy of the Ligand

Kolocouris, Antonios; Hansen, Raino K.; Broadhurst, R. William

doi:10.1021/jm0496685

Cited by 24 publications

(8 citation statements)

References 21 publications

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“…Because there is no barrier for the absorption of amantadine or rimantadine to occupy an interfacial location (Fig. 2 B), these results support the idea that these compounds could first partition into the bilayer before interacting with its target protein (91,92). Moreover, several mutations of the M2 channel (93,94) that confer amantadine resistance to influenza A (at residue positions 26, 27, 30, 31, or 34) are located at a position in the bilayer that could be readily accessible from amantadine that has already absorbed to the interface as well as from the aqueous solution.…”

Section: Implications For Adamantanes As Drugssupporting

confidence: 66%

Distribution and Dynamics of Adamantanes in a Lipid Bilayer

Chew

Guy

Biggin

2008

Biophysical Journal

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The adamantanes are a class of compounds that have found use in the treatment of influenza A and Parkinson's disease, among others. The mode of action for influenza A is based on the adamantanes' interaction with the transmembrane M2 channel, whereas the treatment of Parkinson's disease is thought to relate to a channel block of N-methyl-D-aspartate receptors. An understanding of how these compounds interact with the lipid bilayer is thus of great interest. We used molecular-dynamics simulations to calculate the potential of mean force of adamantanes in a lipid bilayer. Our results demonstrate a preference for the interfacial region of the lipid bilayer for both protonated and deprotonated species, with the protonated species proving significantly more favorable. However, the protonated species have a large free-energy barrier in the center of the membrane. In contrast, there is no barrier (compared with aqueous solution) at the center of the bilayer for deprotonated species, suggesting that the permeant species is indeed the neutral form, as commonly assumed. We discuss the results with respect to proposed mechanisms of action and implications for drug-delivery in general.

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Section: Implications For Adamantanes As Drugssupporting

confidence: 66%

Distribution and Dynamics of Adamantanes in a Lipid Bilayer

Chew

Guy

Biggin

2008

Biophysical Journal

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“…182 The complex was studied in dodecylphosphocholine (DPC) micelles. In earlier work, the lineshape of 1 H resonances of 96 had been utilized 183 and found to give resonances too broad to be detected above pH 7.5, when the open-channel binding of amantadine to the M 2 channel is expected to occur. When using 19 F NMR, this could be circumvented and the authors found that the homotetramer of their fluorinated M 2 TM model peptide appears at pH 7, which is ~ 0.5 units below the pH threshold reported before using CD spectroscopy as the experimental method.…”

Section: The First Hit: Adamantane Derivatives As Antivirals and Amentioning

confidence: 99%

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Wanka¹,

Iqbal²,

Schreiner³

2013

Chem. Rev.

565

475

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“…The synthesis of aminoadamantane compounds 3-9 has been described in ref. [66][67][68][69] , and the synthesis of Table S1). …”

Section: Experimental Protocolmentioning

confidence: 99%

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

Homeyer

Ioannidis

Kolarov

et al. 2016

J. Chem. Inf. Model.

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The development of novel anti-influenza drugs is of great importance because of the capability of influenza viruses to occasionally cross interspecies barriers and to rapidly mutate. One class of anti-influenza agents, aminoadamantanes, including the drugs amantadine and rimantadine now widely abandoned due to virus resistance, bind to and block the pore of the transmembrane domain of the M2 proton channel (M2TM) of influenza A. Here, we present one of the still rare studies that interprets thermodynamic profiles from isothermal titration calorimetry (ITC) experiments in terms of individual energy contributions to binding, calculated by the computationally inexpensive implicit solvent/implicit membrane molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach, for aminoadamantane compounds binding to M2TM of the avian "Weybridge" strain. For all eight pairs of aminoadamantane compounds considered, the trend of the predicted relative binding free energies and their individual components, effective binding energies and changes in the configurational entropy, agrees with experimental measures (ΔΔG, ΔΔH, TΔΔS) in 88, 88, and 50% of the cases. In addition, information yielded by the MM-PBSA approach about determinants of binding goes beyond that available in component quantities (ΔH, ΔS) from ITC measurements. We demonstrate how one can make use of such information to link thermodynamic profiles from ITC with structural causes on the ligand side and, ultimately, to guide decision making in lead optimization in a prospective manner, which results in an aminoadamantane derivative with improved binding affinity against M2TM(Weybridge).

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Interaction between an Amantadine Analogue and the Transmembrane Portion of the Influenza A M2 Protein in Liposomes Probed by¹H NMR Spectroscopy of the Ligand

Cited by 24 publications

References 21 publications

Distribution and Dynamics of Adamantanes in a Lipid Bilayer

Distribution and Dynamics of Adamantanes in a Lipid Bilayer

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

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Interaction between an Amantadine Analogue and the Transmembrane Portion of the Influenza A M2 Protein in Liposomes Probed by1H NMR Spectroscopy of the Ligand

Cited by 24 publications

References 21 publications

Distribution and Dynamics of Adamantanes in a Lipid Bilayer

Distribution and Dynamics of Adamantanes in a Lipid Bilayer

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

Contact Info

Product

Resources

About

Interaction between an Amantadine Analogue and the Transmembrane Portion of the Influenza A M2 Protein in Liposomes Probed by¹H NMR Spectroscopy of the Ligand