#zikaopen: homology models -
TRANSCRIPT
• 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
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
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
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
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
• Twitter: @collabchem
#ZikaOpen