title: Illustrating and homology modeling the proteins of the Zika virus.
abstract: The Zika virus (ZIKV) is a flavivirus of the familyFlaviviridae, which is similar to 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 eitherin vitroorin vivo. ZIKV therefore epitomizes a neglected disease. Several 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 model quality criteria for their further use. 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.
authors.affiliation: Collaborations in Chemistry, Fuquay-Varina, NC, USA; Collaborations Pharmaceuticals Inc., Fuquay-Varina, NC, USA; Collaborative Drug Discovery Inc, Burlingame, CA, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Art of the Cell, Guilford, CT, USA.
authors.forename: John
authors.initials: J
authors.lastname: Liebler
authors.affiliation: LabMol - Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, GO, Brazil.
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Neves
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Warren G
authors.initials: WG
authors.lastname: Lewis
authors.affiliation: The International Rescue Committee, New York, NY, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Coffee
authors.affiliation: RJB Computational Modeling LLC, Chapel Hill, NC, USA.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Bienstock
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Southan
authors.affiliation: LabMol - Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, GO, Brazil.
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
keywords: Aedes mosquito; Zika virus; dengue virus; drug discovery; ebola virus; flavivirus; microcephaly; yellow fever