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 SimulationsClick to copy article linkArticle link copied!
- Athina KonstantinidiAthina KonstantinidiSection of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Athina Konstantinidi
- Nikolaos NazirisNikolaos NazirisSection of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Nikolaos Naziris
- Maria ChountoulesiMaria ChountoulesiSection of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Maria Chountoulesi
- Sophia KiriakidiSophia KiriakidiDepartment of Chemistry, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Sophia Kiriakidi
- Barbara SartoriBarbara SartoriInstitute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9/5, A-8010 Graz, AustriaMore by Barbara Sartori
- Dimitris KolokourisDimitris KolokourisSection of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Dimitris Kolokouris
- Heinz AmentischHeinz AmentischInstitute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9/5, A-8010 Graz, AustriaMore by Heinz Amentisch
- Gregor MaliGregor MaliDepartment of Inorganic Chemistry and Technology, National Institute of Chemistry, Ljubljana SI-1001, SloveniaMore by Gregor Mali
- Dimitrios NtountaniotisDimitrios NtountaniotisDepartment of Chemistry, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Dimitrios Ntountaniotis
- Costas DemetzosCostas DemetzosSection of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Costas Demetzos
- Thomas MavromoustakosThomas MavromoustakosDepartment of Chemistry, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Thomas Mavromoustakos
- Antonios Kolocouris*Antonios Kolocouris*E-mail: [email protected]Section of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Athens 15771, GreeceMore by Antonios Kolocouris
Abstract
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. All three experimental methods pointed out that the two analogues perturbed drastically the DMPC bilayers with AK13 to be more effective at high concentrations. AK13 was tolerated in lipid bilayers at very high concentrations, while Amt was crystallized. This is an important consideration in the formulations of drugs as it designates a limitation of Amt incorporation. MD simulations verify provided details about the strong interactions of the drugs in the interface region between phosphoglycerol backbone and lipophilic segments. The two drugs form hydrogen bonding with both water and sn-2 carbonyls in their amine form or water and phosphate oxygens in their ammonium form. Such localization of the drugs explains the DMPC bilayers reorientation and their strong perturbing effect evidenced by all biophysical methodologies applied.
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