The Location of the Protonated and Unprotonated Forms of Arbidol in the Membrane: A Molecular Dynamics Study

ABSTRACT: Arbidol is a potent broad-spectrum antiviral molecule for the treatment and prophylaxis of many viral infections. Viruses that can be inhibited by arbidol include enveloped and non-enveloped viruses, RNA and DNA viruses, as well as pH-independent and pH-dependent ones. These differences in viral types highlight the broad spectrum of Arb antiviral activity and, therefore, it must affect a common viral critical step. Arbidol incorporates rapidly into biological membranes, and some of its antiviral effects might be related to its capacity to interact with and locate into the membrane. However, no information is available of the molecular basis of its antiviral mechanism/s. We have aimed to locate the protonated (Arp) and unprotonated (Arb) forms of arbidol in a model membrane system. Both Arb and Arp locate in between the hydrocarbon acyl chains of the phospholipids but its specific location and molecular interactions differ from each other. Whereas both Arb and Arp average location in the membrane palisade is a similar one, Arb tends to be perpendicular to the membrane surface, whereas Arp tends to be parallel to it. Furthermore, Arp, in contrast to Arb, seems to interact stronger with POPG than with POPC, implying the existence of a specific interaction between Arp, the protonated from, with negatively charged phospholipids. This data would suggest that the active molecule of arbidol in the membrane is the protonated one, i.e., the positively charged molecule. The broad antiviral activity of arbidol would be defined by the perturbation it exerts on membrane structure and therefore membrane functioning. GRAPHICAL ABSTRACT: [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00232-016-9876-3) contains supplementary material, which is available to authorized users.