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#ZikaOpen: Homology Models -

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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.

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#ZikaOpen: Homology Models -

  1. 1. #ZikaOpen: Homology Models Image by John Liebler
  2. 2. HTTP://WWW.VIPRBRC.ORG/BRC/HOME.SPG?DECORATOR=FLAVI_ZIKA Zika is here but we are not ready for it
  3. 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. 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. 5. GLYCOPROTEIN E Initially modelled based on Dengue trimer crystal structure Minimized in Discovery Studio
  6. 6. DOCKING Previous work by others on Dengue pointed to location for interaction Used to dock MicroSource molecules
  7. 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. 8. COLLABORATIONS WITH SCIENTISTS IN BRAZIL
  9. 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. 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. 11. ARTICLE & PREPRINT • Submitted to F1000Research • Also immediately posted on figshare
  12. 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. 13. • Klein et al., Illustration for Dengue virus Klein et al., J Virol. 2013 Feb;87(4):2287-93. GLYCOPROTEIN E FUNCTION
  14. 14. OTHER PROTEINS IN ZIKA
  15. 15. GLYCOPROTEIN E DIMER CONFORMATION HOMOLOGY MODEL
  16. 16. JOHN’S BLOG Images by John Liebler
  17. 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. 18. NS5
  19. 19. FTSJ
  20. 20. NS4B • Only partial template coverage
  21. 21. NS4A • Only partial template coverage
  22. 22. HELICc
  23. 23. DEXDc
  24. 24. PEPTIDASE S7
  25. 25. NS2B • Only partial template coverage
  26. 26. NS2A • Only partial template coverage
  27. 27. NS1
  28. 28. E STEM
  29. 29. GLYCOPROTEIN M
  30. 30. PROPEP
  31. 31. CAPSID Only partial template coverage
  32. 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. 33. • This work has not been funded • Please contact any of us to contribute time, effort, molecules • ekinssean@yahoo.com • Twitter: @collabchem #ZikaOpen
  34. 34. ACKNOWLEDGEMENTS Tom Stratton Priscilla L. Yang

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