Alchemical Free Energy Calculations and Isothermal Titration Calorimetry Measurements of Aminoadamantanes Bound to the Closed State of Influenza A/M2TM

Harris Ioannidis, Antonios Drakopoulos, Christina Tzitzoglaki, Nadine Homeyer, Felix Kolarov, Paraskevi Gkeka, Kathrin Freudenberger, Christos Liolios, Günter Gauglitz, Zoe Cournia, Holger Gohlke (Lead / Corresponding author), Antonios Kolocouris (Lead / Corresponding author)

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Abstract

Adamantane derivatives, such as amantadine and rimantadine, have been reported to block the transmembrane domain (TM) of the M2 protein of influenza A virus (A/M2) but their clinical use has been discontinued due to evolved resistance in humans. Although experiments and simulations have provided adequate information about the binding interaction of amantadine or rimantadine to the M2 protein, methods for predicting binding affinities of whole series of M2 inhibitors have so far been scarcely applied. Such methods could assist in the development of novel potent inhibitors that overcome A/M2 resistance. Here we show that alchemical free energy calculations of ligand binding using the Bennett acceptance ratio (BAR) method are valuable for determining the relative binding potency of A/M2 inhibitors of the aminoadamantane type covering a binding affinity range of only 2 kcal mol-1. Their binding affinities measured by isothermal titration calorimetry (ITC) against the A/M2TM tetramer from the Udorn strain in its closed form at pH 8 were used as experimental probes. The binding constants of rimantadine enantiomers against M2TMUdorn were measured for the first time and found to be equal. Two series of alchemical free energy calculations were performed using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids to mimic the membrane environment. A fair correlation was found for DPPC that was significantly improved using DMPC, which resembles more closely the DPC lipids used in the ITC experiments. This demonstrates that binding free energy calculations by the BAR approach can be used to predict relative binding affinities of aminoadamantane derivatives toward M2TM with good accuracy.

Original languageEnglish
Pages (from-to)862-876
Number of pages15
JournalJournal of Chemical Information and Modeling
Volume56
Issue number5
Early online date22 Apr 2016
DOIs
Publication statusPublished - 23 May 2016

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Rimantadine
Calorimetry
Titration
Free energy
contagious disease
Amantadine
Phosphorylcholine
energy
Lipids
acceptance
Adamantane
Derivatives
Proteins
Enantiomers
experiment
Viruses
Experiments
Ligands
Membranes
simulation

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Ioannidis, Harris ; Drakopoulos, Antonios ; Tzitzoglaki, Christina ; Homeyer, Nadine ; Kolarov, Felix ; Gkeka, Paraskevi ; Freudenberger, Kathrin ; Liolios, Christos ; Gauglitz, Günter ; Cournia, Zoe ; Gohlke, Holger ; Kolocouris, Antonios. / Alchemical Free Energy Calculations and Isothermal Titration Calorimetry Measurements of Aminoadamantanes Bound to the Closed State of Influenza A/M2TM. In: Journal of Chemical Information and Modeling. 2016 ; Vol. 56, No. 5. pp. 862-876.
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abstract = "Adamantane derivatives, such as amantadine and rimantadine, have been reported to block the transmembrane domain (TM) of the M2 protein of influenza A virus (A/M2) but their clinical use has been discontinued due to evolved resistance in humans. Although experiments and simulations have provided adequate information about the binding interaction of amantadine or rimantadine to the M2 protein, methods for predicting binding affinities of whole series of M2 inhibitors have so far been scarcely applied. Such methods could assist in the development of novel potent inhibitors that overcome A/M2 resistance. Here we show that alchemical free energy calculations of ligand binding using the Bennett acceptance ratio (BAR) method are valuable for determining the relative binding potency of A/M2 inhibitors of the aminoadamantane type covering a binding affinity range of only 2 kcal mol-1. Their binding affinities measured by isothermal titration calorimetry (ITC) against the A/M2TM tetramer from the Udorn strain in its closed form at pH 8 were used as experimental probes. The binding constants of rimantadine enantiomers against M2TMUdorn were measured for the first time and found to be equal. Two series of alchemical free energy calculations were performed using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids to mimic the membrane environment. A fair correlation was found for DPPC that was significantly improved using DMPC, which resembles more closely the DPC lipids used in the ITC experiments. This demonstrates that binding free energy calculations by the BAR approach can be used to predict relative binding affinities of aminoadamantane derivatives toward M2TM with good accuracy.",
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Ioannidis, H, Drakopoulos, A, Tzitzoglaki, C, Homeyer, N, Kolarov, F, Gkeka, P, Freudenberger, K, Liolios, C, Gauglitz, G, Cournia, Z, Gohlke, H & Kolocouris, A 2016, 'Alchemical Free Energy Calculations and Isothermal Titration Calorimetry Measurements of Aminoadamantanes Bound to the Closed State of Influenza A/M2TM', Journal of Chemical Information and Modeling, vol. 56, no. 5, pp. 862-876. https://doi.org/10.1021/acs.jcim.6b00079

Alchemical Free Energy Calculations and Isothermal Titration Calorimetry Measurements of Aminoadamantanes Bound to the Closed State of Influenza A/M2TM. / Ioannidis, Harris; Drakopoulos, Antonios; Tzitzoglaki, Christina; Homeyer, Nadine; Kolarov, Felix; Gkeka, Paraskevi; Freudenberger, Kathrin; Liolios, Christos; Gauglitz, Günter; Cournia, Zoe; Gohlke, Holger (Lead / Corresponding author); Kolocouris, Antonios (Lead / Corresponding author).

In: Journal of Chemical Information and Modeling, Vol. 56, No. 5, 23.05.2016, p. 862-876.

Research output: Contribution to journalArticle

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AU - Ioannidis, Harris

AU - Drakopoulos, Antonios

AU - Tzitzoglaki, Christina

AU - Homeyer, Nadine

AU - Kolarov, Felix

AU - Gkeka, Paraskevi

AU - Freudenberger, Kathrin

AU - Liolios, Christos

AU - Gauglitz, Günter

AU - Cournia, Zoe

AU - Gohlke, Holger

AU - Kolocouris, Antonios

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