Illustrating and homology modeling the proteins of the Zika virus

Abstract

The Zika virus (ZIKV) is a flavivirus of the family , which is similar to Flaviviridae dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either or . ZIKV therefore epitomizes a neglected disease. Several in vitro in vivo suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our criteria for selection. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

An Overview on Zika Virus and the Importance of Computational Drug Discovery

“…74 Ekins and colleagues modeled all 15 proteins of ZIKV (NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E) using homology modeling methodology, 75 providing a detailed structural knowledge of ZIKV for further understanding of its genomic, proteomic and molecular mechanisms to aid in the development of drug discovery. Molecular docking is a versatile approach in drug discovery, and could provide an informational, accruable geometry and stable interaction of the ligand within the targeted protein.…”

Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins

“…In particular, a plethora of results has been achieved through comparative, or homology, modeling principles [32,33]. In addition to the global structural genomics, an initiative that focuses on determining the 3D structures of individual proteins on a genome scale [34], as well as to the specific efforts aimed at rapid structural characterization of proteins in emerging viruses [35][36][37][38], multiple works have used comparative modeling to predict the structures of protein-protein interaction complexes [39][40][41], facilitate structure-based drug discovery [33,42,43], infer protein functions [44], determine the macromolecular interaction network [45][46][47][48], and provide molecular insights into the viral evolution [49][50][51].…”

Zika Virus, Microcephaly and its Possible Global Spread

“…For research purposes, it has been suggested that the famous adenosine analog NITD008 that has been used in the past against other viruses [110][111][112] also has the antiviral activity both in vitro and in vivo against Zika virus [113]. Now, the sequences and in some cases the crystal structure of different important Zika virus proteins are available and they can be targeted through computational drug designing techniques [114][115][116][117]. Similarly, the already available data on the closely related viruses like dengue virus enzymes can be exploited for novel drug design [118].…”