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The adamantanes are a class of compounds that have found use in the treatment of influenza A and Parkinson's disease, among others. The mode of action for influenza A is based on the adamantanes' interaction with the transmembrane M2 channel, whereas the treatment of Parkinson's disease is thought to relate to a channel block of N-methyl-D-aspartate receptors. An understanding of how these compounds interact with the lipid bilayer is thus of great interest. We used molecular-dynamics simulations to calculate the potential of mean force of adamantanes in a lipid bilayer. Our results demonstrate a preference for the interfacial region of the lipid bilayer for both protonated and deprotonated species, with the protonated species proving significantly more favorable. However, the protonated species have a large free-energy barrier in the center of the membrane. In contrast, there is no barrier (compared with aqueous solution) at the center of the bilayer for deprotonated species, suggesting that the permeant species is indeed the neutral form, as commonly assumed. We discuss the results with respect to proposed mechanisms of action and implications for drug-delivery in general.

Original publication

DOI

10.1529/biophysj.108.139477

Type

Journal article

Journal

Biophys J

Publication Date

15/12/2008

Volume

95

Pages

5627 - 5636

Keywords

Absorption, Adamantane, Cell Membrane, Lipid Bilayers, Models, Molecular, Molecular Conformation, Protons