Characterizing the Ligand-Binding Landscape of Zika NS3 Helicase-Promising Lead Compounds As Potential Inhibitors

Abstract

Aim: This study aims to provide insight into the binding features of the ATPase and ssRNA sites of the NS3 helicase. Methods: Clinically approved Flavivirus inhibitors were docked to the corresponding active sites of the protein, and the three best compounds were validated with molecular dynamic simulations. Result: Binding of Ivermectin to ssRNA site and Lapachol and HMC-HO1α to the ATPase site allowed for conformational rigidity of the Zika NS3 helicase, thus stabilizing residue fluctuations and allowing for protein stability. Favorable free binding energies were also noted between compounds and the helicase, thus supporting the intermolecular forces at the helicase active site. Conclusion: The pharmacophoric characteristics found in Lapachol, HMC-HO1α and Ivermectin may be utilized in the design of a potent hybrid drug that is able to show efficient inhibition of a multitude of diseases including the detrimental co-infection of Zika virus, dengue and chikungunya.