Features of the electrostatic interaction of methylene blue with the protein coat of flaviviruses

Among the many pharmacological properties of methylene blue, its antiviral activity against enveloped viruses, including flaviviruses, is well known. Flaviviruses pose a global threat to human health. This group of viruses includes Zika virus, which causes severe developmental disabilities when infected in utero, and dengue virus, which accounts for a significant proportion of all cases of diseases caused by flaviviruses. In this study, we created a complete map of methylene blue interactions with the protein coats of two flaviviruses. For the first time, Brownian dynamics analysis was used to analyze the interactions of methylene blue with amino acid residues of the Zika and dengue virus envelope proteins, which are involved in the early stages of cell infection, and to identify interactions that may underline the compound's known antiviral activity. It was found that a large region of negative potential surrounding the glycan loop of the Zika virus envelope protein effectively attracts methylene blue molecules, while the dengue virus glycan loop is shielded from electrostatic interactions with methylene blue by a region of positive potential. In turn, the loop of the dengue virus envelope protein, which mediates the primary binding of viruses to cells, can form a significant number of contacts with methylene blue molecules, which is not observed for a similar loop in the Zika virus envelope protein. Molecular modeling methods allowed us to theoretically substantiate the inhibitory effect of methylene blue on the early stages of the enveloped virus life cycle, which include primary recognition of the host cell surface and membrane fusion, as known from experimental studies.