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Open zika presentation

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

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Open zika presentation

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 11. • Klein et al., Illustration for Dengue virus Klein et al., J Virol. 2013 Feb;87(4):2287-93. GLYCOPROTEIN E FUNCTION
  12. 12. Other proteins IN ZIKA
  13. 13. GLYCOPROTEIN E DIMER conformation HOMOLOGY MODEL
  14. 14. JOHN’S BLOG Images by John Liebler
  15. 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. 16. Comparing Flavivirus cryo-EM’s
  17. 17. Then why not model every protein • Used Swissmodel • Took a few hours over weekend.
  18. 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. 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. 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. 21. It is a global research collaboration project Our main goal is to accelerate the discovery of an effective treatment for Zika virus
  22. 22. Virtual screening of millions of compounds 20 millions compounds 90 millions compounds How WCG will contribute to this research?
  23. 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. 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. 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. 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. 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. 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. 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. 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. 31. press
  32. 32. • This work has not been funded • Please contact any of us to contribute time, effort, molecules • ekinssean@yahoo.com • Twitter: @collabchem #ZikaOpen
  33. 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. 34. OPENZIKA https://www.worldcommunitygrid .org/
  35. 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. 36. And more…. Tom Stratton Priscilla L. Yang

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