Interaction of Flaviviruses with Reproduction Inhibitors Binding in β-OG Pocket: Insights from Molecular Dynamics Simulations

Flaviviral diseases, including dengue fever, West Nile fever, yellow fever, tick-borne encephalitis, Omsk haemorrhagic fever, and Powassan encephalitis, threaten human health all over the world. Lack of effective antivirals targeting replication cycle of flaviviruses makes the search of such compounds a challenging task. Recently we have identified a reproduction inhibitor effective against tick-borne encephalitis virus and Powassan virus (POWV) (ACS Med. Chem. Lett., 2013, 4, 869-874). To enable using this inhibitor as a template for 3D pharmacophore search, a biologically active conformation of this molecule should have been established. Here we performed molecular dynamics simulations of the complexes between the different enantiomers of the inhibitor and POWV envelope (E) proteins, putative targets of the inhibitor, in the different protonation states corresponding to the different stages of membrane fusion process. Several stable conformations of the inhibitor were identified, opening routes for further design of more advanced molecules.