Identification of Potential Lead Molecules for Zika Envelope Protein from In Silico Perspective

Abstract

Background: Zika virus is the family member of flavivirus with no reported clinically approved drugs or vaccines in the market till date. This virus is spread by Aedes mosquitoes, and can also be transmitted through sexual contact or blood transfusions. There are reported medical conditions like microcephaly among new-borns delivered by infected pregnant women. The envelope protein of Zika virus is associated with virulence, tropism, mediation of receptor binding and membrane fusion. ED1-EDII domain (K1 loop pocket) is an integral part of the envelope protein and a potential drug target. In the present study, the purpose was to identify the potential lead molecules to dock against K1 loop which could be later considered as flavivirus entry inhibitors.

Methods: Multiple sequence alignment method was considered for the analysis of indels in envelope protein. Phylogenetic tree was constructed based on the alignment. Aliphatic index, GRAVY scores and hydropathy plot of the envelope proteins were calculated for the flavivirus family members. Zika envelope protein was homology modeled and considered for protein-ligand docking analysis with chemical compounds of known functions.

Results: As per in silico based analysis, the envelope protein of Zika virus is highly hydrophilic with the least number of amino acid deletions compared to rest of the family members. During docking studies, it was observed that compounds like NITD, compound 6, P02, Doxytetracycline and Rolitetracycline show better binding affinity with Zika envelope protein compared to dengue virus.

Conclusion: These better binding compounds could be the promising lead molecules for Zika envelope protein which could better block the viral entry.

Keywords: Aedes; Dengue virus; Envelope protein; Flavivirus; Microcephaly; Zika virus.

Figure 1.

Multiple sequence alignment of yellow fever, Japanese encephalitis, West Nile, Zika and dengue envelope proteins. The identical, conservative and non-conservative substitutions are shown as asterisk (*), colon (:) and dot (.), respectively. Deletions were denoted as hyphen (-).

Figure 2.

The pairwise alignment of the K1 loop of dengue and Zika envelope proteins (268–280) highlighting the region of identical and semi-conservative residues which are critically involved in drug interaction.

Figure 3.

The rooted phylogenetic tree generated using Clustal Omega software for Japanese encephalitis (P27395), dengue (P17763), West Nile (P06935), yellow fever (P03314) and Zika (Q32ZE1) envelope proteins.

Figure 4.

Hydrophobicity analysis using Kyte-Doolittle hydropathy plot for envelope proteins of (a) Zika (b) dengue (c) Japanese encephalitis (d), West Nile (e) and yellow fever.

Figure 5.

A) Ramachandran plot of modeled Zika envelope protein. B) PROSA showing the local model quality of the modeled Zika protein. The plot is generated with a window size of 40.

Figure 6.

The docked poses of ligands A1–A5 with the envelope protein of dengue (a–e). The interactions between compound 6, Doxycycline, NITD, PO2 and Rolitetracycline (f–j). The purple color denotes hydrogen bond donor and the green color denotes hydrogen bond acceptor.

Figure 7.

The docked poses of ligands A1–A5 with the envelope protein of Zika (a–e). The interactions between compound 6, Doxycycline, NITD, PO2 and Rolitetracycline (f–j). The purple color denotes hydrogen bond donor and the green color denotes hydrogen bond acceptor