In silico prediction of phosphorylation of NS3 as an essential mechanism for Dengue virus replication and the antiviral activity of Quercetin

Abstract

Infection by Dengue virus is a global health problem for which there have been challenges to obtaining a cure. Current vaccines can only be narrowly applied in ongoing clinical trials. We employed computational methods to predict therapeutic efficacy based on structure-function relationships between human host kinases and viral Nonstructural Protein 3(NS3) in an effort to understand the therapeutic effect of inhibitors of viral replication. Phosphorylation at each of two most evolutionarily conserved sites, S137 and T189 compared to the unphosphorylated state were studied with molecular dynamics and docking simulations. The simulations suggested that phosphorylation at S137 caused a greater structural change than phosphorylation at T189. Docking studies supported the idea that phosphorylation at S137 increased the binding affinity between NS3 and NS5,whereas, phosphorylation at T189 decreased it. The interaction of NS3 and NS5is essential for viral replication. Docking studies with the antiviral plant flavonoid Quercetin with NS3 indicated that Quercetin physically occluded theS137 phosphorylation site. Taken together these findings suggest a specific site and mechanism by which Quercetin inhibits Dengue and possible other flaviviruses.