Molecular mechanism of ATP and RNA binding to Zika virus NS3 helicase and identification of repurposed drugs using molecular dynamics simulations

Congenital Zika virus syndrome has caused a public health emergency of international concern. So far, there are no drugs available to prevent or treat the infection caused by Zika virus. The Zika virus NS3 helicase is a potential protein target for drug discovery due to its vital role in viral genome replication. NS3 helicase unwinds the viral RNA to enable the reproduction of the viral genome by the NS5 protein. NS3 helicase has two crucial binding sites; the ATP binding site and the RNA binding site. We used molecular docking and molecular dynamics (MD) simulations to study the structural behavior of Zika virus NS3 helicase in its apo form and in the presence of ATP, single-stranded RNA, and both ATP-RNA to understand their potential implications in NS3 helicase activity. Further, we have carried out virtual screening of FDA approved drugs, followed by molecular docking to identify the ATP-competitive hit molecules as probable Zika virus NS3 helicase inhibitors. The MD simulations trajectories were analyzed using normal mode analysis and principal component analysis that reveals fluctuations in the R-loop. These findings aid in understanding the molecular mechanisms of the simultaneous binding of ATP and RNA, and guide the design and discovery of new inhibitors of the Zika virus NS3 helicase as a promising drug target to treat the Zika virus infection.