Molecular dynamics simulations of allosteric motions and competitive inhibition of the Zika virus helicase

The 2015 Zika outbreak sparked major global concern and emphasized the reality and dangers still posed by mosquito borne pathogens. While efforts have been made to develop a vaccine and other therapeutics, there is still a great demand for antiviral drugs targeting Zika and other flaviviruses. The non-structural protein 3 (NS3) helicase is a vital component of the viral replication complex, tasked with unwinding the viral dsRNA molecule into single strands. Given this critical function, the Zika virus helicase is a potential therapeutic target and the focus of many ongoing research efforts. Using a combination of drug docking and molecular dynamics simulations, we have identified a list of competitive helicase inhibitors targeting the ATP hydrolysis site and have discovered a potential allosteric site capable of distorting both of the protein's active sites.