Vector-borne flaviviruses like dengue, West Nile, yellow fever, Japanese encephalitis, tick-borne encephalitis, and Zika virus are important human pathogens responsible for a high health and economic burden worldwide. Despite the urgent need, no antivirals for the prevention or treatment of flavivirus infections and mitigation of future outbreaks are currently available. While flaviviruses protease are structurally conserved and compounds with broad spectrum activity have been reported in the literature, most of the research focuses on the study of inhibitors targeting one virus at a time. Pan-flavivirus inhibitors would be extremely valuable as they would allow the treatment of several flavivirus infections with just one pill. This project aims to study the interaction of different protease inhibitors in complex with proteases from several flaviviruses. Compounds will be docked to the available structures of NS2B/NS3 proteases from different flaviviruses and the binding stability over time and affinity will be evaluated from analysis of molecular dynamics simulations trajectories. The study of interactions between the flavivirus non-structural protein NS4B and known inhibitors will also be studied. Currently, no crystal structures of NS4B are available as its hydrophobic nature makes crystallization and structure solution challenging. We aim to perform MD simulations with models of NS4B (generated using homology modeling and alphafold) in complex with potent inhibitors reported in the literature. This second project will be performed together with collaborators from Professor Ralf Bartenschlager's lab at the Department of Molecular Virology, Heidelberg University.