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. 2024;42(19):9873-9891.
doi: 10.1080/07391102.2023.2252929. Epub 2023 Sep 15.

Mutational analyses, pharmacophore-based inhibitor design and in silico validation for Zika virus NS3-helicase

Laxman Durgam  1 , Jishu Pagag  1 , Y Indra Neela  1 , Lalitha Guruprasad  1
Affiliations

Mutational analyses, pharmacophore-based inhibitor design and in silico validation for Zika virus NS3-helicase

Laxman Durgam et al. J Biomol Struct Dyn. 2024.

Abstract

Zika virus is responsible for causing Zika infections and was declared as a public health emergency of international concern in February 2016. The Zika virus NS3-helicase is a viable drug target for the design of inhibitors due to its essential role in the replication of viral genome. The viral RNA is unwound by the NS3-helicase in order to enable the reproduction of viral genome by the NS5 protein. Zika virus infections in humans are being reported for the last 15 years. We have therefore carried out amino acid mutational analyses of NS3-helicase. NS3-helicase has two crucial binding sites: the ATP and RNA binding sites. The cofactor-ATP based pharmacophore was generated for virtual screening of ZINC database using Pharmit server, that is followed by molecular docking and molecular dynamics simulations of potential hits as probable Zika virus NS3-helicase inhibitors at the cofactor binding site. The drug-like properties of the molecules were analysed and, DFT calculations were performed on the five best molecules to reveal their stability in solvent phase compared to gas phase, the HOMO and LUMO and electrostatic potential maps to analyze the electronic and geometric characteristics. These are significant findings towards the discovery of new inhibitors of Zika virus NS3-helicase, a promising drug target to treat the Zika virus infection.Communicated by Ramaswamy H. Sarma.

Keywords: DFT; HOMO; LUMO; Zika virus NS3-helicase; binding free energy; drug-like properties; molecular docking; molecular dynamics simulations; mutational analyses; pharmacophore.

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