open zika presentation

Prof. Carolina Horta Andrade, Ph.D.

carolina@ufg.brhttp://openzika.ufg.br

Alexander Perryman, Ph.D.Alex.L.Perryman@njms.rutgers.edu

Sean Ekins, Ph.D.collaborationspharma@gmail.com

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

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

http://www.viprbrc.org/brc/home.spg?decorator=flavi_zika

By Jan ‘16 -Zika is here but we are not ready for it

• 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

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

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

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??

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)

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

• Klein et al.,

Illustration for Dengue virus

Klein et al., J Virol. 2013 Feb;87(4):2287-93.

GLYCOPROTEIN E FUNCTION

Other proteins IN ZIKA

GLYCOPROTEIN E DIMER conformation HOMOLOGY MODEL

JOHN’S BLOG

Images by John Liebler

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

publishedJohn produced images of both Zika and Dengue

Zika appears ‘Pimplier’Dimer has narrow letter box grooveDengue has a bigger pore between intersection of 5 dimersDoes this help us understand how drugs could access virus?Does it help understand function?Opportunities for vaccine design?

Images by John Liebler

Comparing Flavivirus cryo-EM’s

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

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

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.

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.

It is a global research collaboration project

Our main goal is to accelerate the discovery of an effective treatment for Zika virus

Virtual screening of millions of compounds

20 millions compounds90 millions compounds

How WCG will contribute to this research?

MAIN GOALInnovative project to discover a new anti-viral drug to treat patients

infected with the Zika virusGenes or targets involved in a diseaseChemical space (library)

Drug candidates for Zika virus

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

NS1 (5iy3) and HM protein

RMSD: 0.896 Å

NS1 (5k6k) and HM proteinRMSD: 0.812 Å

Glycoprotein E (5jhm) and HM proteinRMSD: 1.860 Å

NS2B/NS3 (5jrz) and HM protein (peptidase S7)

RMSD: 0.824 Å

Comparison Homology Modeling X Crystal Structures

NS3 helicase5jmt and HM (HELICc) proteinRMSD: 0.732 Å

NS3 helicase (FP strain)5jrz and HM (HELICc) proteinRMSD: 0.746 Å

NS3 helicase5jmt and HM (DEXDc) proteinRMSD: 0.894 Å

NS3 helicase (FP strain)5jrz and HM (DEXDc) proteinRMSD: 0.830 Å

Comparison Homology Modeling X Crystal Structures

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)

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: purplePredicted binding mode 2: cyan

Crystal binding mode 1: purplePredicted binding mode 1: greenAutoDock Vina

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 OZhave been identified

NS3 helicase (PDB ID 5jmt)

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

press

• This work has not been funded• Please contact any of us to contribute time, effort,

molecules• ekinssean@yahoo.com• Twitter: @collabchem

#ZikaOpen

WHAT IF WEVolunteered our computers and phones to..

1.24 billion docking jobs submitted

11,734 CPU years of crunching time

And it cost $0Source: WCG

We've docked ~ 6 million compounds

OPENZIKAhttps://www.worldcommunitygrid.org/

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

And more….

Tom Stratton

Priscilla L. Yang