|By: The OpenZika research team|
|3 Nov 2016|
The OpenZika researchers are ready to begin laboratory testing for five chemical compounds which may lead to potential treatments. In this update, the research team discusses why the search for an anti-Zika drug is so important, describes the process of choosing which drug compounds to test, and summarizes the work they and IBM have done (so far) to publicize this study.
The OpenZika project is searching for drug candidates to treat the Zika virus in people who have been infected. The project is targeting key proteins that the Zika virus likely uses to survive and spread in the body. In order to develop an anti-Zika drug, researchers need to identify which of millions of chemical compounds might be effective at interfering with these key proteins. The effectiveness of each compound is being tested in virtual experiments, called “docking calculations,” performed on World Community Grid volunteers’ computers and Android devices. These calculations are helping the research team focus on the most likely compounds that may eventually lead to an antiviral medicine.
The importance of the search for an antiviral drug
Even though several labs are doing cell-based screens with drugs already approved by the US Food and Drug Administration (FDA) agency, few to none of the “hit” compounds that have been identified thus far are both potent enough against Zika virus and also safe for pregnant women. These other labs are performing “High Throughput Screens” (HTS) in a wet-lab setting; the rapid nature of those assays can cause a lot of “false negative results” (that is, active compounds can be accidentally mistaken for duds).
In some experiments, we are also docking the FDA approved drugs, but in addition we are docking the drugs approved in the European Union and the set of “NIH clinical candidates” (which gives our set a size of 7,600 advanced compounds, as opposed to just testing around 800 to 1,500 FDA approved drugs). In addition, our other experiments involve docking a much larger set of 6 million different commercially available (not as advanced or optimized) “hit- and lead-like” compounds, which could lay the foundation for future drug development studies.
Our virtual screens can also produce false negative and false positive results, but when we identify a small number of candidate compounds for our collaborators to test in wet-lab cell-based assays, their assays can then be performed in a lower throughput, in a more accurate manner.
As far as we know, all the labs are still a long way from discovering new anti-Zika drugs, and we all need to work together and pursue different and complementary approaches. In addition, based on our experience with how other viruses eventually evolve drug resistance to evade treatment, the world will likely need to discover several different types of drugs against Zika that can be used in a combination therapy, in order to slow down the evolution of “super bug” versions of it.
There are a number of efforts underway to develop a vaccine against the Zika virus. However, vaccines do not help people who already have the infection. Although vaccine development progress is being made, it will take several years before they are proven effective and safe, and before enough doses can be mass produced and distributed. Even after approved vaccines are available and distributed to the public, not all people will be vaccinated. Consequently, in the meantime and in the future, cures for Zika infections are needed.
Progress on choosing compounds for lab testing
ZIKV NS3 helicase with three candidate inhibitors selected by virtual screening, shown as solvent-accessible surfaces, with different shades of green. The identification of these candidates and the video were made by Dr. Alexander L. Perryman.
We began the analysis phase of the project by focusing on the results against the apo NS3 helicase crystal structure (apo means that the protein was not bound to anything else, such as a cofactor, inhibitor, or nucleic acid). This NS3 helicase is a component of the Zika virus that allows it to replicate. In the first screening results that we examined, approximately 7,600 compounds in a composite library composed of the US Food and Drug Administration-approved drugs + the drugs approved in the European Union + the US National Institutes of Health clinical collection library were docked against this helicase. Below are the results of this screening:
- 150 compounds passed the energetic and interaction-based docking filters, and their predicted binding modes were inspected and measured in detail.
- Of the compounds that were inspected in detail, 16 compounds passed this visual inspection stage of their docked modes
- From the compounds that passed the visual inspection, 8 passed subsequent medicinal chemistry-based inspection
- 6 of these could be ordered (1 cost over $100.00 per milligram (and we generally need at least 10 milligrams for the quality control process and the assays) and 1 was restricted by the US Drug Enforcement Agency)
Subsequently, five of the six compounds we purchased passed quality control studies to verify their identity and purity. These five compounds were recently sent to the University of California San Diego for in vitro testing against Zika virus by Dr. Jair L. Siqueira-Neto, one of the researchers for OpenZika.
For more information about these experiments, please visit our website.
Also, we are currently visually inspecting approximately 260 additional compounds that passed a larger and more diverse set of docking filters against the new RNA-bound NS3 helicase crystal structure (using the same composite library of the drugs approved in the U.S. and the E.U. + the NIH clinical candidates). A dozen new candidates have been identified thus far.
Searching for additional collaborators
We are looking for new collaborators who can provide complementary skillsets. Specifically, we are looking for labs who can help with different types of cell-based assays and, especially, enzyme-based assays of the Zika virus proteins. Dr. Siqueira-Neto performs a couple types of cell-based assays, but several different approaches are being developed to test compounds against Zika (and each type of assay has its own strengths and weaknesses). Having results from different types of assays is helpful when evaluating our candidate compounds.
Our PLoS Neglected Tropical Diseases paper, "OpenZika: An IBM World Community Grid Project to Accelerate Zika Virus Drug Discovery," was published on October 20, and it has already been viewed over 2,100 times. Another research paper, titled “Illustrating and homology modeling the proteins of the Zika virus,” is hopefully close to being finally accepted. Perhaps these articles will help bring additional attention to the project and encourage the formation of new collaborations.
We recently created a storefront on Zazzle with the OpenZika logo on many different items such as T-shirts, polo shirts, mugs, buttons, mouse pads, and phone cases. Zazzle determined the base price of the items, and we then set 10% of the base price as our "profit,” which will all be donated toward compound purchasing and testing for the OpenZika project. At the same time, wearing attire that has the OpenZika logo helps spread the word. And nerd art is fun to have.
The OpenZika team is working on grants from the National Institutes of Health, CNPq (a Brazilian funding agency), and other organizations to try raise funds for purchasing and testing compounds.
We have been working hard to promote the project, and continue to look for additional opportunities. Below is a list of our most recent outreach efforts.
- Carolina Andrade, Sean Ekins, and Alex Perryman teamed up with Reddit Science for an Ask Me Anything about the science behind the OpenZika project.
- Sean Ekins gave an invited presentation at North Carolina State to chemistry students and faculty and discussed OpenZika.
- Carolina Andrade gave an invited lecture at Federal University of Bahia, Brazil, to pharmacy students and the general public regarding Emergent Flavoviruses and OpenZika.
Recent press mentions or interviews
The launch of OpenZika attracted a great deal of attention. Below are a few of the major press mentions about the project.
"Rutgers researchers using power of Web to help stop Zika" (North Jersey News)
"Rutgers scientists aiding in Zika research project" (Washington Times)
"Fighting the Zika virus with the power of supercomputing" (World Pharma News)
"'Everyone Wants to Contribute:' Rutgers Scientists Aid in Zika Research" (NBC Philadelphia)
"International Business Machines Corp Jumps to Fight Zika Virus; Here’s How" (Business Finance News)
"Zika! Computational Biology to the Rescue" Biomedical Computation Review
"Rutgers University scientists want public to help with Zika research” (New Jersey News)
We are very grateful for all of the volunteers who are donating their unused computing time to this project! Thank you very much!!