#zikaopen: homology models -

#ZikaOpen: Homology Models

Image by John Liebler

HTTP://WWW.VIPRBRC.ORG/BRC/HOME.SPG?DECORATOR=FLAVI_ZIKA

Zika is here but we are not ready for it

• Common responses:

• Concern for effects of drug on pregnant women

• Zika virus is mild

• Will wait for a vaccine

• But:

• It is sexually transmitted

• There are severe neurological issues for some

• We are still waiting for vaccines for HIV, malaria, TB etc

Little visibility for antiviral efforts against Zika

HOW IT STARTED FOR ME

• Discussion with Antony

Williams and others

• Initially was not sure what

could be done – Jan 26th

Email discussion with

Priscilla L. Yang suggested

glycoprotein E– Jan 27th

• Analysis of sequence

• Swiss Model

GLYCOPROTEIN E

Initially modelled based on

Dengue trimer crystal structure

Minimized in Discovery Studio

DOCKING

Previous work by others on

Dengue pointed to location for

interaction

Used to dock MicroSource

molecules

COMMUNICATION

• I reached out on Twitter and blog to enlist

ideas and help

• Emailed program officers at NIH NIAID

• Also proposed that open repositories be

created and journals waive charges for

papers

• Several scientists responded

• Connected to collaborators

• Started writing up a white paper

• Used GoogleDocs to collaborate

COLLABORATIONS WITH SCIENTISTS IN BRAZIL

Proposed workflow for rapid drug discovery against Zika virus

Ekins S, Mietchen D, Coffee M et al. 2016 [version 1; referees: awaiting peer review]

F1000Research 2016, 5:150 (doi: 10.12688/f1000research.8013.1)

Ekins S, Mietchen D, Coffee M et al. 2016 [version 1; referees: awaiting peer review]

F1000Research 2016, 5:150 (doi: 10.12688/f1000research.8013.1)

Compounds and chemical libraries suggested for testing against Zika virus

ARTICLE & PREPRINT

• Submitted to

F1000Research

• Also immediately

posted on figshare

ART OF THE CELL

• Contacted by John Liebler

• He wanted to illustrate the virus!

• This got me thinking about the

complete virus

• Needed to read up on flavivirus

mechanism

• After a few days realized he

needed a different

conformation of glycoprotein E

• Klein et al.,

Illustration for Dengue virus

Klein et al., J Virol. 2013 Feb;87(4):2287-93.

GLYCOPROTEIN E FUNCTION

OTHER PROTEINS IN ZIKA

GLYCOPROTEIN E DIMER CONFORMATION HOMOLOGY MODEL

JOHN’S BLOG

Images by John Liebler

SPOT THE DIFFERENCE

John produced images of both Zika and Dengue

Zika appears ‘Pimplier’

Dimer has narrow letter box groove

Dengue has a bigger pore between intersection of 5 dimers

Does this help us understand how drugs could access virus?

Does it help understand function?

Opportunities for vaccine design?Images by John Liebler

NS4B

• Only partial template coverage

NS4A


HELICc

PEPTIDASE S7

NS2B


NS2A


E STEM

GLYCOPROTEIN M

PROPEP

CAPSID

Only partial template coverage

WHAT NEXT…

• Minimize proteins, identify binding sites - how many can we target?

• Large scale docking, FDA drugs, known antivirals, bigger libraries e.g. Zinc

• May need large scale computing

• Analyze results – select and purchase compounds

• May need to look at combinations – can we model computationally

• Testing of compounds

• Generate machine learning models from screening data

• Write grants to support work in Brazil

• Assemble a complete model of virus with models

• Work with groups to crystallize proteins

• This work has not been funded

• Please contact any of us to contribute time, effort,

molecules

• [email protected]

• Twitter: @collabchem

#ZikaOpen

ACKNOWLEDGEMENTS

Tom Stratton

Priscilla L. Yang

#zikaopen: homology models -

Science