|The Smallpox Protection Project|
Questions and Answers
Q. What is smallpox?
The smallpox or variola virus is the most virulent member of the orthopox genus of viruses. It is specific for humans and has no other animal hosts. Smallpox was eliminated from the world in 1977 however stocks of the variola virus are known to exist and its use as a weapon of bioterrorism remains a frightening possibility. The availability of drugs to counter the virus would be a major defense.
Q. Why develop a cure for smallpox? There is already a vaccine.
The vaccine is very successful in eradicating the variola virus but the vaccine does have serious side effects. There are, on average, two deaths per million vaccinations and several hundred people could have serious side effects. Additionally, people whose immune system is not functioning correctly must not be given the vaccine. These would include young children, pregnant mothers and those on certain medications. It is also suggested that a “weapons grade” smallpox virus may be different from the natural variola virus. In fact, the US government is stock piling a different strain of the vaccinia virus compared with the one UK government has started collecting.
Q. I had the vaccine, so why do I need a protection drug?
Everyone would have to be vaccinated again for complete protection of the general population. The vaccine immunity fades over a prolonged time period and whole population scale vaccination was stopped 30 years ago.
Q. Why a drug, not a better vaccine?
It takes time for a vaccine to activate the immune system via the production of antibodies; during that time the vaccine offers no protection. So a drug would be useful for an emergency situation. Vaccination is only preventive, not a cure.
Q. What would the drug that you are trying to find do?
We hope to block the chemistry of an enzyme, which unwinds tightly coiled DNA. Viruses often package their DNA as super-coiled DNA, so that it is small enough for transport. Uncoiling of this DNA is required for the virus to replicate. Blocking the enzyme will stop the virus from replicating.
Q. Is this enzyme present in the human body and are there any additional benefits of finding it?
The virus has its own version so we are targeting that. But we will also check the results against the human version too. If we can block the chemistry of the human version, then this could be very interesting as the result could possibly act as an anti-cancer drug. Some cancers have their DNA super-coiled so the drug may help to slow cancer replication and growth as well. Therefore this project will also look at anti-cancer protein targets. Screensaver participants will be allowed to choose whether they do both projects or continue the main project only.
About the project
Q. How many molecules is this project screening? Against how many protein targets?
We shall be looking at 35 million compounds. These are well-known drug-like compounds, which can either be bought or easily made. These drug-like molecules can be readily acquired as smallpox drugs if good candidates are found. These molecules will be screened against 9 protein models, representing two different potential binding sites.
Q. How long will the project last?
We don’t know the answer to this until we start. We will be using the LigandFit drug discovery software, to screen 35 million molecules against 9 protein models. The similar Anthrax project, which used the THINK software, took 23 days to screen 3.5 billion molecules against 1 protein target.
Q. What does LigandFit software do?
The LigandFit software used in phase 2 of the cancer project and this research project calculates the interaction energy of the molecule with the target active site of the protein. The lower the energy the better the drug candidate.
Q. What are hits?
A hit is recorded if there is a negative binding energy, which is then reported as a positive score. That is to say that the molecule-protein complex is of lower energy than the molecule and protein not bound together.
Q. Are the results ranked?
Yes, there is a scoring function, which takes into account the amount of the negative binding energy, pharmacophore matching and solvent effects.
Q. What happens next?
The top ranked drug candidates would be synthesized or purchased and tested against the vaccinia virus, which is a prototype of the orthopox genus of viruses. Its genetic sequence is similar to the variola virus but doesn’t lead to disease in humans. In the absence of three-dimensional structures for variola proteins, it should be possible to substitute those obtained from the highly similar vaccinia virus and thus achieve the same results.
Q. Who is funding this research?
The Smallpox Research Grid Project is funded by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and our corporate sponsor, IBM. Accelrys and Evotec OAI have donated their technology and services while researchers at Oxford and Essex Universities, the Robarts Research Institute, The University of Western Ontario and the Sloan-Kettering Cancer Center are leading the research and providing their expertise.
Q. Who gets the results?
The ranked list of hits will be provided to the U.S. Department of Defense, who has contracted with United Devices for this Project through the U.S. Army Medical Research Institute of Infectious Diseases and potentially other allied governments (e.g., UK government, Canadian government) as directed by the US government, so that they also can take the “hits” and further process and develop them to help combat the use of smallpox as a bioterrorist threat or military weapon. It is essential that in blocking the action of smallpox the related human enzyme is not affected so the binding to that human target will also be tested.
Q. How might a successful drug be used?
A drug against the smallpox virus could be used to protect aid workers and in an emergency, those infected with the virus. Also, when made universally available, it would remove the threat of biological terrorism with the smallpox virus.
Q. Could it be used to develop weapons?
No, it would stop the biochemistry of the virus from working.
Q. How do we know it will not be used in biological weapons research?
Nearly every country has signed treaties not to conduct biological weapons research. Inspections will check that governments are not using it for biological weapons research projects.
Q. How do I know you will actually do useful and scientifically valid computations on my computer?
United Devices is working on this project with many highly visible, well-respected organizations and research institutions. Please feel free to review the web sites of each of these organizations to confirm their involvement.
In addition, our members can see the project themselves via the UD Agent interface. UD is committed to Member involvement—Members will always have information about the project that their machines are working on.
About Running the UD Agent and Participating in the Project
Q. If the UD Agent is using my computer's resources, will this affect my regular computer use?
No. Configured correctly, the UD Agent will never interfere with your ability to use your own computer. Most computers never use all of their resources-it is estimated that up to 90% of the processing power of an individual PC goes unused. The United Devices distributed computing model is based on the ability to utilize this "idle" capacity from individual computers.
Q. Do I have to leave my computer on all the time for this to work? Or always be online?
The UD Agent can run only when your computer is on, but it will automatically start when you start your computer. The more your computer is on, the more processing happens. The UD Agent doesn't need to be connected to the Internet to work its task, but once finished, it needs to reconnect to return data and to get a new task to work on.
Q. Can people running the UD Agent choose which projects they participate in?
Yes, Members will always be told what projects they are running and have the option of opting out of a project by simply deselecting it on the device profile page. They will also have access to Web pages outlining which organizations are providing the project applications and explaining those projects.
Q. Can I choose which molecules or proteins that I want to work on?
No, these are organized to best perform and track the research. The system does not allow for selection of research components.
Q. What is contained in the files I send back to the United Devices servers?
Each result set contains the 3D molecular structures and corresponding scores generated during the screening process. This data is important in the result post-processing phase of the cancer project.
Q. How many conformations does each molecule go through?
Each molecule is different, and the number of conformations differs molecule to molecule. Some molecules may be more complex, or have more flexibility, and thus will have more conformations.
Q. What's the difference between a conformer and a de novo structure?
Conformers are molecules with the same molecular structure (same number of atoms and same atoms are bonded within the molecule) but with a different 3-Dimension representation due to twisting of various internal bonds. A de novo structure, or de novo derivative, is a molecule that has actually been altered slightly rather than just contorted.
Q. Why does the protein look so different from the molecule? Where are the atoms and/or bonds in the protein?
There may be thousands of atoms in any one of the target proteins; it often makes sense to visualize the complete protein structure using "space-fill" representations.
In comparison to one of our target proteins containing some 3000+ atoms, an example drug-like molecule being considered may consist of a mere 20-50 atoms—imagine how tiny the drug-like molecule would be if we displayed it on screen using the same scale as that for the protein!
What About Security?
Q. Is it safe? What are the security risks of downloading the UD Agent software?
There are security risks in every application downloaded from the Internet, period. However, we take security very seriously at United Devices. We have a comprehensive system of technology and policies to protect you, your computer, and the data running on it. The measures that we use include, but are not limited to, virus scanning all of our build environments, digitally signing information sent to the UD Agent, encryption both of locally stored files and files sent to the UD Agent, and biometric access control to the United Devices servers. We do everything we can to keep both the UD Agent and our server systems as secure as possible.
Q. Will my privacy be compromised?
web site by Karl Harrison Department of Chemistry, University of Oxford