Proposed lead molecules against Hemagglutinin of avian influenza virus (H5N1)

Tannistha Nandi

doi:10.6026/97320630002240

Abstract

Human infection with avian influenza H5N1 is an emerging infectious disease characterized by respiratory symptoms and a high fatality rate. Hemagglutinin and neuraminidase are the two surface proteins responsible for infection by influenza virus. Till date, neuraminidase has been the major target for antiviral drugs. In the present study we chose hemagglutinin protein as it mediates the binding of the virus to target cells through sialic acid residues on the host cell-surface. Hemagglutinin of H5 avian influenza (PDB ID: 1JSN) was used as the receptor protein. Ligands were generated by structure-based de novo approach and virtual screening of ZINC database. A total of 11,104 conformers were generated and docked into the receptor binding site using 'High Throughput Virtual Screening'. We proposed potential lead molecules against the receptor binding site of hemagglutinin based on the results obtained from in silico docking and hydrogen bond interaction between the ligand and the 1JSN protein molecule. We found sialic acid derivative 1 to be the lead molecules amongst the ligands generated by structure based de novo approach. However the molecules obtained from ZINC database were showing better docking scores as well as conserved hydrogen bond interactions. Thus we proposed ZINC00487720 and ZINC00046810 as potential lead molecules that could be used as an inhibitor to the receptor binding site of hemagglutinin. They could now be studied in vivo to validate the in silico results.

Highlights

Influenza virus belongs to the Orthomyxoviridae family, which consists of four genera: Influenza A virus, Influenza B Virus, Influenza C virus and Thogotovirus [1] Influenza A virions are enveloped and contain eight segments of single-stranded, negative-sense RNA, which encode 11 proteins [1]
We studied the docking interaction of derivatives of sialic acid, galactose and Nacetyl glucosamine molecules at the active site of avian H5 hemagglutinins
We proposed lead molecules that competitively bind the active site of HA, prevent its attachment to the host cell surface moieties, and might serve as a good antiviral drug to control influenza virus infection

Summary

Background

Influenza virus belongs to the Orthomyxoviridae family, which consists of four genera: Influenza A virus, Influenza B Virus, Influenza C virus and Thogotovirus [1] Influenza A virions are enveloped and contain eight segments of single-stranded, negative-sense RNA, which encode 11 proteins [1]. Two licensed influenza antiviral agents are recommended for use in the United States during the 200708 influenza season: oseltamivir and zanamivir These are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses [6]. We analyzed the binding site of avian H5 hemagglutinins (HAs) from avian influenza virus to human cell receptor analogs. We studied the docking interaction of derivatives of sialic acid, galactose and Nacetyl glucosamine molecules at the active site of avian H5 hemagglutinins. We proposed lead molecules that competitively bind the active site of HA, prevent its attachment to the host cell surface moieties, and might serve as a good antiviral drug to control influenza virus infection.

Most attention has been directed toward the type A

HA from influenza virus A belonging to all known HA

We had screened the obtained ligand conformers by high

It was shown that the monosaccharide sialic acid cannot

Conclusion: