These slides provide a complete and upto date analysis of the project and complement the recent article in PLOS Neglected Tropical Diseases

1. Prof. Carolina Horta Andrade, Ph.D.
carolina@ufg.br
http://openzika.ufg.br
Alexander Perryman, Ph.D.
Alex.L.Perryman@njms.rutgers.edu
Sean Ekins, Ph.D.
collaborationspharma@gmail.com

2. How it started
• SE discussion with Antony
Williams and others
• Blogged about Zika in Jan
• Took hashtag #ZikaOpen in Jan
• ‘Asked’ for tropical disease
voucher for Zika
• 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

3. Communication
• 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

4. http://www.viprbrc.org/brc/home.spg?decorator=flavi_zika
By Jan ‘16 -Zika is here but we are not ready for it

5. • 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

6. CDC report: http://www.cdc.gov/zika/geo/active-countries.html
Zika Global Crisis
Confirmed in + of 50 countries
WHO said that ZIKV may spread in Europe
this summer.
Microcephaly and other neurological
issues
Zika virus (ZIKV) - reported in 1947
Neglected until 2015
May, 2015 - outbreak in Brazil that
quickly has spread to the Americas

7. Zika virus (ZIKV)
http://viralzone.expasy.org/all_by_species/6756.html
Virion
Enveloped, spherical, about 50 nm in
diameter. The surface proteins are
arranged in an icosahedral-like
symmetry.
Genome

8. Proposed workflow for rapid drug discovery against Zika virus
Ekins, S. et al., Open Drug Discovery for the Zika Virus. F1000Research
2016, 5, 1–12 (doi: 10.12688/f1000research.8013.1)
SBDD or LBDD??

9. Compounds and chemical libraries suggested for testing against ZIKV
Ekins, S. et al., Open Drug Discovery for the Zika Virus. F1000Research
2016, 5, 1–12 (doi: 10.12688/f1000research.8013.1)

10. Art of THE CELL
• After first paper was published…
• 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

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

12. Other proteins IN ZIKA

13. GLYCOPROTEIN E DIMER
conformation HOMOLOGY MODEL

14. JOHN’S BLOG
Images by John Liebler

15. Spot the Difference – and we did this over a month
before cryo-EM structures were published
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

16. Comparing Flavivirus cryo-EM’s

17. Then why not model every protein
• Used Swissmodel
• Took a few hours over weekend.

18. ZIKV strain (GenBank)
SWISS-MODEL server
Selection: Global Model Quality
Estimation (GMQE) and QMEAN statistical
parameters
Stereochemical quality -> PROCHECK
NS5 (A), FtsJ (B), HELICc (C), DEXDc (D), Peptidase S7
(E), NS1 (F), E Stem (G), Glycoprotein M (H),
Propeptide (I), Capsid (J), and Glycoprotein E (K)
Ekins, S.; et al., Illustrating and Homology Modeling the Proteins
of the Zika Virus. F1000Research 2016, 5, 275.
Homology Modeling

19. Stereochemical quality: PROCHECK
15 proteins -> 11 proteins
NS5 (A), FtsJ (B), HELICc (C), DEXDc (D), Peptidase
S7 (E), NS1 (F), E Stem (G), Glycoprotein M (H),
Propeptide (I), Capsid (J), and Glycoprotein E (K)
Homology Modeling
Ekins, S.; et al., Illustrating and Homology Modeling the Proteins
of the Zika Virus. F1000Research 2016, 5, 275.

20. How it OpenZika started
Dr. Sean Ekins Dr. Alex Perryman
IBM philanthropic initiative, launched in 2004, that provides massive
supercomputing power for scientists, without any costs, by using the idle
processing power of computer or Android devices of volunteers.

21. It is a global research collaboration project
Our main goal is to accelerate the discovery of an effective
treatment for Zika virus

22. Virtual screening of millions of compounds
20 millions compounds
90 millions compounds
How WCG will contribute to this research?

23. MAIN GOAL
Innovative project to discover a new anti-viral drug to treat patients
infected with the Zika virus
Genes or targets involved in a diseaseChemical space (library)
Drug candidates for Zika virus

24. Envelope Glycoprotein (PDB ID: 5JHM)
NS1 protein (PDB ID: 5IY3, 5K6K)
NS3 helicase (PDB ID:5JMT, 5JRZ)
NS2B/NS3 protease (PDB ID: 5LC0)
ZIKV protein Crystallographic structures

25. NS1 (5iy3) and
HM protein
RMSD: 0.896 Å
NS1 (5k6k)
and HM protein
RMSD: 0.812 Å
Glycoprotein E (5jhm)
and HM protein
RMSD: 1.860 Å
NS2B/NS3 (5jrz)
and HM protein (peptidase S7)
RMSD: 0.824 Å
Comparison Homology Modeling X Crystal Structures

26. NS3 helicase
5jmt and HM (HELICc) protein
RMSD: 0.732 Å
NS3 helicase (FP strain)
5jrz and HM (HELICc) protein
RMSD: 0.746 Å
NS3 helicase
5jmt and HM (DEXDc) protein
RMSD: 0.894 Å
NS3 helicase (FP strain)
5jrz and HM (DEXDc) protein
RMSD: 0.830 Å
Comparison Homology Modeling X Crystal Structures

27. OpenZika = # crunching for a cure
 Building on GO FAM experience, to develop & hone new
workflows  creating a new platform for time & cost
efficient responses to emerging infectious diseases
 Screening millions of compounds vs. Zika, Dengue, West
Nile, Yellow Fever, JEV, HCV (with some targets from Mtb,
Klebsiella pneum., Pseudomonas aeur., and Bacillus anthracis)
Ekins, S., Perryman, A.L., & Andrade, C. PLoS NTD (Oct. 20, 2016)

28. Positive Controls:
NS5 class: 2 binding sites
Site 1: related to the ligand 2′-deoxy-2′-fluoro-
2′-methyluridine 5′-(trihydrogen diphosphate)
position
Site 2: related to the ligand S-Adenosyl
Methionine (SAM) position
DOCKING
Crystal binding mode 2: purple
Predicted binding mode 2: cyan
Crystal binding mode 1: purple
Predicted binding mode 1: greenAutoDock Vina

29.  Identified 15 candidates
for assays (from library of
7,628 approved drugs & clinical
candidates)
 These are predicted to
bind the (apo) ZIKV NS3
helicase (3 of the 15 are
shown above)
 After medicinal chemistry
inspection, we selected 8
to order & assay (but 1 is
too expensive, and 1 is
restricted by the DEA)
 5 of the 6 we ordered
passed LC/MS quality
control & will be assayed
at UCSD
1st candidates from OZ
have been identified
NS3 helicase (PDB ID 5jmt)

30. Timeline
Mid-May – Oct. 6, 2016:
 60,000 volunteers donated CPU time from ~ 240,000 devices
 >11,000 CPU years have been donated to OpenZika
 1.242 billion different docking jobs have been submitted
 207 binding sites on 138 different protein targets are involved
 2-5 different binding sites are targeted / protein
 6 million compounds are docked against each site
 11 million out of a new library of 38 million compounds have been prepared
for future docking experiments
 739 million docking results have been sent back to our server
 Currently visually inspecting the docking results against the
NS3 helicase:RNA complex  13 new candidates identified

31. press

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

33. WHAT IFWE
Volunteered our computers and phones to..
1.24 billion docking jobs submitted
11,734 CPU years of crunching time
And it cost $0
Source: WCG
We've docked ~ 6 million compounds

34. OPENZIKA
https://www.worldcommunitygrid
.org/

35. Our Team
Be a WCG volunteer and help our research!!! We need you!
http://openzika.ufg.br
Carolina Andrade Sean EkinsAlex Perryman
Rodolpho Braga Melina Mottin Roosevelt Silva Wim Degrave Ana Carolina Ramos João Herminio
Lucio Freitas Jr.Jair Lage Joel Freundlich

36. And more….
Tom Stratton
Priscilla L. Yang