Comparative Perturbation Effects Exerted by the Influenza A M2 WT Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2'-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations.

  title={Comparative Perturbation Effects Exerted by the Influenza A M2 WT Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2'-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations.},
  author={Athina Konstantinidi and Nikolaos Naziris and Maria Chountoulesi and Sophia Kiriakidi and Barbara Sartori and Dimitris Kolokouris and Heinz Amentisch and Gregor Mali and Dimitrios Ntountaniotis and Costas Demetzos and Thomas M. Mavromoustakos and Antonios Kolocouris},
  journal={The journal of physical chemistry. B},
  volume={122 43},
Aminoadamantane drugs are lipophilic amines that block the membrane-embedded influenza A M2 WT (wild type) ion channel protein. The comparative effects of amantadine ( Amt) and its synthetic spiro[pyrrolidine-2,2'-adamantane] (AK13) analogue in dimyristoylphosphatidylcholine (DMPC) bilayers were studied using a combination of experimental biophysical methods, differential scanning calorimetry (DSC), X-ray diffraction, solid-state NMR (ssNMR) spectroscopy, and molecular dynamics (MD) simulations… 
Influenza A M2 Spans the Membrane Bilayer, Perturbs its Organization and Differentiates the Effect of Amantadine and Spiro[pyrrolidine-2,2'-adamantane] AK13 on Lipids
The investigation and observations made for the M2TM, excess aminoadamantane ligands in DMPC were made using the simpler version of biophysical methods including SDC, SAXS and WAXS, MD simulations
Chemical Probes for Blocking of Influenza A M2 WT and S31N Channels.
In the active M2 S31N blockers 1 and 6, the phenyl and isoxazolyl head groups achieve a deeper binding position, corresponding to high kon / low koff and high koff measured rate constants, compared to inactive 2-5, which have much lower kon and higher koff.
(2-Hydroxy-4-methoxy)benzyl Aminoadamantane Conjugates as Probes to Investigate Specificity Determinants in Blocking Influenza M2 S31N and M2 WT Channels with Binding Kinetics and Simulations
<p>In an attempt to synthesize potent blockers of the influenza A M2 S31N proton channel with modifications of amantadine, we used MD simulations and MM-PBSA calculations to project binding modes of
Supramolecules in Drug Discovery and Drug Delivery: Methods and Protocols
This chapter shows a protocol for the preparation of drug:CDcomplex delivery systems, which are enhancing bioavailability and solving problems of absorption for poorly soluble lipophilic drugs by forming water-soluble inclusion complexes.
A Differential Scanning Calorimetry (DSC) Experimental Protocol for Evaluating the Modified Thermotropic Behavior of Liposomes with Incorporated Guest Molecules.
A protocol for DSC measurements onliposomal systems with incorporated guest molecules is described and a prediction of the behavior of potential future drug delivery liposomal platforms is predicted.
Chimeric Stimuli-Responsive Liposomes as Nanocarriers for the Delivery of the Anti-Glioma Agent TRAM-34
The chimeric nanoplatforms presented herein have shown promise for biomedical applications so far and should be further studied in terms of their ability to deliver TRAM-34 and other therapeutic molecules to glioblastoma cells.


Drug-induced conformational and dynamical changes of the S31N mutant of the influenza M2 proton channel investigated by solid-state NMR.
Solid-state NMR spectroscopy is used to investigate the effects of one of these isoxazole compounds, WJ352, on the conformation of the S31N TM segment and the dynamics of the proton-selective residue, His37, suggesting that the drug is significantly stabilized by hydrophobic interactions between the adamantane and the TM peptide.
Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2.
Simulation results indicate that amantadine has a strong, specific orientation with the amine turned inward toward the central cavity in the S31 M2 pore but has variable orientation and a strong propensity to remain outward pointing in N31 M 2, which might contribute to its inefficacy as an inhibitor of the mutant protein.
Structure of the Amantadine Binding Site of Influenza M2 Proton Channels In Lipid Bilayers
Solid-state NMR spectroscopy indicates that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses and demonstrates the ability of solid- state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes.
Solid-state NMR and MD simulations of the antiviral drug amantadine solubilized in DMPC bilayers.
The interactions of (15)N-labeled amantadine with DMPC bilayers were investigated by solid-state NMR and by a 12.6-ns molecular dynamics simulation, finding the drug was found to assume a single preferred orientation and location when incorporated in these bilayers.
Free Energy Calculations Reveal the Origin of Binding Preference for Aminoadamantane Blockers of Influenza A/M2TM Pore.
Free Energy Perturbation calculations coupled with Molecular Dynamics simulations (FEP/MD) are used to rationalize the thermodynamic origin of binding preference of several aminoadamantane derivatives inside the A/M2TM pore and demonstrate that this methodology holds predictive value and can be used to guide the optimization of drug candidates binding to membrane proteins.
Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2.
The power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable are demonstrated.
Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus
This work has discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine’s potency against WT M2, and contains a charged ammonium group.
Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations
It is demonstrated how one can make use of such information to link thermodynamic profiles from ITC with structural causes on the ligand side and to guide decision making in lead optimization in a prospective manner, which results in an aminoadamantane derivative with improved binding affinity against M2TM(Weybridge).
Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.
Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M1S31N.
Alchemical Free Energy Calculations and Isothermal Titration Calorimetry Measurements of Aminoadamantanes Bound to the Closed State of Influenza A/M2TM
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).