tetano
Editor, Senior Moderator
J Am Chem Soc. 2016 Jan 25. [Epub ahead of print]
[h=1]Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel.[/h] Wright AK, Batsomboon P, Dai J, Hung I, Zhou HX, Dudley GB, Cross TA.
[h=3]Abstract[/h] Rimantadine hydrochloride (α-methyl-1-adamantane-methalamine hydrochloride) is a chiral compound which exerts antiviral activity against the Influenza A virus by inhibiting proton conductance of the M2 ion channel. In complex with M2, rimantadine has always been characterized as a racemic mixture. Here we report the novel enantioselective synthesis of deuterium-labeled (R)- and (S)-rimantadine and the characterization of their protein-ligand interactions using solid-state NMR. Isotropic chemical shift changes strongly support differential binding of the enantiomers to the proton channel. Position restrained simulations satisfying distance restraints from [SUP]13[/SUP]C-[SUP]2[/SUP]H rotational-echo double-resonance (REDOR) NMR show marked differences in the hydrogen bonding pattern of the two enantiomers at the binding site. Together these results suggest a complex set of interactions between (R)-rimantadine and the M2 proton channel, leading to a higher stability for this enantiomer of the drug in the channel pore.
PMID: 26804976 [PubMed - as supplied by publisher]
[h=1]Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel.[/h] Wright AK, Batsomboon P, Dai J, Hung I, Zhou HX, Dudley GB, Cross TA.
[h=3]Abstract[/h] Rimantadine hydrochloride (α-methyl-1-adamantane-methalamine hydrochloride) is a chiral compound which exerts antiviral activity against the Influenza A virus by inhibiting proton conductance of the M2 ion channel. In complex with M2, rimantadine has always been characterized as a racemic mixture. Here we report the novel enantioselective synthesis of deuterium-labeled (R)- and (S)-rimantadine and the characterization of their protein-ligand interactions using solid-state NMR. Isotropic chemical shift changes strongly support differential binding of the enantiomers to the proton channel. Position restrained simulations satisfying distance restraints from [SUP]13[/SUP]C-[SUP]2[/SUP]H rotational-echo double-resonance (REDOR) NMR show marked differences in the hydrogen bonding pattern of the two enantiomers at the binding site. Together these results suggest a complex set of interactions between (R)-rimantadine and the M2 proton channel, leading to a higher stability for this enantiomer of the drug in the channel pore.
PMID: 26804976 [PubMed - as supplied by publisher]