Towards Molecular Dynamics Simulation of Membrane-Targeting Photosensitizing Antivirals

Abstract

Recent pandemics emphasize the importance of broad-spectrum antivirals, since most small-molecule drugs targeting the specific viral machinery rapidly become ineffective due to resistance development. Amphiphilic photosensitizers, one class of such antivirals, can damage the lipid membranes of enveloped viruses much more efficiently than those of our cells — thanks to the lack of lipid antioxidant systems in viruses. Still, knowledge of the exact mechanisms behind the antiviral activity of such compounds is lacking. In this work, we use our previously published data on the antiviral activity of a series of perylene analogues to uncover the structure–activity relationships using molecular dynamics simulations inside explicit lipid bilayers. Our results suggest that the hydrophobic/hydrophilic nature of the substituent can lever the singlet-oxygen-producing perylene core by colocalizing it with the double bond layer of the phospholipids’ unsaturated chain. This relationship opens the way for a future design strategy of perylene-based antivirals to maximize their efficiency.