tetano
Editor, Senior Moderator
J Phys Chem B. 2018 Oct 4. doi: 10.1021/acs.jpcb.8b07071. [Epub ahead of print]
[h=1]Comparative Perturbation Effects Exerted by the Influenza M2 Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2'-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations.[/h] Konstantinidi A, Naziris N, Chountoulesi M, Kiriakidi S, Sartori B, Kolokouris D, Amentisch H, Mali G, Ntountaniotis D, Demetzos C, Mavromoustakos T, Kolocouris A.
[h=3]Abstract[/h] Aminoadamantane drugs are lipophilic amines that bind to membrane embedded influenza A WT M2 protein. The comparative effects of the M2 WT channel blockers amantadine (Amt) and its synthetic spiro[pyrrolidine-2,2'-adamantane] (AK13) analog in dimyristoylphosphatidylcholine DMPC bilayers were studied using a combination of experimental biophysical methods, Differential Scanning Calorimetry (DSC), X-ray diffraction, solid-state NMR (ssNMR) and molecular dynamics simulations (MD). All three experimental methods pointed out that the two analogs 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 glycerol backbone and lipophilic segments. Drugs topographical position re-orients the DMPC bilayers and form hydrogen bonding with both water and sn-2 carbonyls or phosphate oxygens. Such localization of the drugs explains their strong perturbing effect evidenced by all biophysical methodologies applied.
PMID: 30285441 DOI: 10.1021/acs.jpcb.8b07071
[h=1]Comparative Perturbation Effects Exerted by the Influenza M2 Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2'-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations.[/h] Konstantinidi A, Naziris N, Chountoulesi M, Kiriakidi S, Sartori B, Kolokouris D, Amentisch H, Mali G, Ntountaniotis D, Demetzos C, Mavromoustakos T, Kolocouris A.
[h=3]Abstract[/h] Aminoadamantane drugs are lipophilic amines that bind to membrane embedded influenza A WT M2 protein. The comparative effects of the M2 WT channel blockers amantadine (Amt) and its synthetic spiro[pyrrolidine-2,2'-adamantane] (AK13) analog in dimyristoylphosphatidylcholine DMPC bilayers were studied using a combination of experimental biophysical methods, Differential Scanning Calorimetry (DSC), X-ray diffraction, solid-state NMR (ssNMR) and molecular dynamics simulations (MD). All three experimental methods pointed out that the two analogs 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 glycerol backbone and lipophilic segments. Drugs topographical position re-orients the DMPC bilayers and form hydrogen bonding with both water and sn-2 carbonyls or phosphate oxygens. Such localization of the drugs explains their strong perturbing effect evidenced by all biophysical methodologies applied.
PMID: 30285441 DOI: 10.1021/acs.jpcb.8b07071