This presentation summarizes some early efforts on an open drug discovery collaboration between scientists in Brazil and the US. The amazing virus images were created by John Liebler and can be licensed from him http://www.artofthecell.com/animation/will-the-real-zika-virus-please-stand-up The homology models were created with Swiss Model by Sean Ekins: Marco Biasini, Stefan Bienert, Andrew Waterhouse, Konstantin Arnold, Gabriel Studer, Tobias Schmidt, Florian Kiefer, Tiziano Gallo Cassarino, Martino Bertoni, Lorenza Bordoli, Torsten Schwede. (2014). SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Research; (1 July 2014) 42 (W1): W252-W258; doi: 10.1093/nar/gku340. Arnold K., Bordoli L., Kopp J., and Schwede T. (2006). The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling. Bioinformatics, 22,195-201. Kiefer F, Arnold K, Künzli M, Bordoli L, Schwede T (2009). The SWISS-MODEL Repository and associated resources. Nucleic Acids Research. 37, D387-D392. Guex, N., Peitsch, M.C., Schwede, T. (2009). Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: A historical perspective. Electrophoresis, 30(S1), S162-S173.

1. #ZikaOpen: Homology Models
Image by John Liebler

2. HTTP://WWW.VIPRBRC.ORG/BRC/HOME.SPG?DECORATOR=FLAVI_ZIKA
Zika is here but we are not ready for it

3. • 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

4. 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

5. GLYCOPROTEIN E
Initially modelled based on
Dengue trimer crystal structure
Minimized in Discovery Studio

6. DOCKING
Previous work by others on
Dengue pointed to location for
interaction
Used to dock MicroSource
molecules

7. 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

8. COLLABORATIONS WITH SCIENTISTS
IN BRAZIL

9. 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)

10. 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

11. ARTICLE & PREPRINT
• Submitted to
F1000Research
• Also immediately
posted on figshare

12. 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

13. • Klein et al.,
Illustration for Dengue virus
Klein et al., J Virol. 2013 Feb;87(4):2287-93.
GLYCOPROTEIN E FUNCTION

14. OTHER PROTEINS IN ZIKA

15. GLYCOPROTEIN E DIMER CONFORMATION
HOMOLOGY MODEL

16. JOHN’S BLOG
Images by John Liebler

17. 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

18. NS5

19. FTSJ

20. NS4B
• Only partial template coverage

21. NS4A
• Only partial template coverage

22. HELICc

23. DEXDc

24. PEPTIDASE S7

25. NS2B
• Only partial template coverage

26. NS2A
• Only partial template coverage

27. NS1

28. E STEM

29. GLYCOPROTEIN M

30. PROPEP

31. CAPSID
Only partial template coverage

32. 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

33. • This work has not been funded
• Please contact any of us to contribute time, effort,
molecules
• ekinssean@yahoo.com
• Twitter: @collabchem
#ZikaOpen

34. ACKNOWLEDGEMENTS
Tom Stratton
Priscilla L. Yang