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> GO Fight Against Malaria, подбор белков для блокировки малярийного плазмодия
Rilian
Nov 20 2011, 14:35
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Проект "GO Fight Against Malaria"

Проект запущен 15 Ноября 2011

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Как присоединиться читайте в главном топике World Community Grid thumbsup.gif

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Дата основания команды - 28.02.2005 Капитан - rilian
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О проекте:

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Mission
The mission of the GO Fight Against Malaria project is to discover promising drug candidates that could be developed into new drugs that cure drug resistant forms of malaria. The computing power of World Community Grid will be used to perform computer simulations of the interactions between millions of chemical compounds and certain target proteins, to predict their ability to eliminate malaria. The best compounds will be tested and further developed into possible treatments for the disease.

Significance
Malaria is one of the three deadliest infectious diseases on earth and is caused by parasites that infect both humans and animals. Female mosquitoes spread the disease by biting infected hosts and passing the parasites to other hosts that they bite later. When these parasites replicate themselves in red blood cells (which the parasites use for food), the symptoms of malaria appear. Malaria initially causes fevers and headaches, and in severe cases it leads to comas or death. Plasmodium falciparum, the parasite that causes the deadliest form of malaria, kills more people than any other parasite on the planet. Over 3 billion people are at risk of being infected with malaria.

Although there are many approved drugs that are able to cure malarial infections, multi-drug-resistant mutant "superbugs" exist that are not eliminated by the current drugs. Because new mutant superbugs keep evolving and spreading throughout the world, discovering and developing new types of drugs that can cure infections by these multi-drug-resistant mutant strains of malaria is a significant global health priority.

Approach
Scientists at The Scripps Research Institute of La Jolla, California, U.S.A., will use IBM's World Community Grid to computationally evaluate millions of candidate compounds against different molecular drug targets from the malaria parasite. If these target molecules can be disabled, then patients infected with malaria can potentially be cured. The computations will estimate the ability of the candidate compounds to disable the particular target molecules needed by the malaria parasite to survive and multiply. Particular priority will be given to targets and candidate compounds which could attack the multi-drug-resistant mutant "superbug" strains of the malaria parasite. The power of World Community Grid can reduce to one (1) year what would take at least one hundred (100) years to complete using the resources normally available to the researchers at The Scripps Research Institute. The results computed on World Community Grid will be available in the public domain for all scientists to use and build upon in their research to develop drugs to fight malaria.

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Malaria is one of the three deadliest infectious diseases on Earth. The other two are HIV and tuberculosis. Plasmodium falciparum, the parasite that causes the deadliest form of malaria, kills more people than any other parasite on the planet. Half of the entire human population is at risk of being infected. In 2006, 247 million people became infected with malaria. Of the nearly one million deaths caused by malaria each year, 85% of those killed are children. In fact, it is the leading cause of death in Africa for those under five years of age: every 30 seconds another child dies of malaria. Even if malaria does not kill the infected person, it still causes impaired learning, absences in schools, lost work and increased poverty - effects that can last a lifetime. Where it is widespread, it can account for 40% of all public health costs. Thus, according to the World Health Organization, malaria is both a disease of poverty and a cause of poverty.

Even though malaria predominantly infects people in Africa, South-East Asia, and South America, in this era of globalization, it affects almost all sub-populations of the world, either physically, mentally, or monetarily. Millions of people from developed countries visit malaria-infested regions each year, and thus are exposed to malaria. As the global climate continues to change, the regions in which this disease flourishes could expand, since a mere half-degree Celsius increase in temperature can produce a 30-100% increase in the abundance of mosquitoes, which are the vectors that transmit malaria to humans.

Malaria is a disease that can actually be completely cured - not just "treated". Although there are many approved drugs that are able to cure malarial infections, multi-drug-resistant mutant "superbug" strains exist that are not being eliminated by the drugs currently available. Being "resistant" to a drug means that the specific target protein molecule, whose activity the drug blocks, has mutated (changed), which makes the drug lose its effectiveness at treating the infection. But at the same time, the mutation does not prevent the superbug from surviving and reproducing. The World Health Organization's 2001 report on "Drug Resistance in Malaria" indicates that the parasite Plasmodium falciparum has already developed resistance to nearly all anti-malaria drugs. As of 2004, drug resistance has reduced the usefulness of all currently available anti-malaria drugs, except for the artemisinin derivatives. Consequently, artemisinin derivatives have become a critical component of the recommended combination therapies. Unfortunately, malaria parasites resistant to artemisinin and its derivatives have recently started to appear at the Thai-Cambodian border. Because new mutant superbugs keep evolving and spreading throughout the world, discovering and developing new types of drugs that can eliminate these multi-drug-resistant mutants is a significant global health necessity.

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The GO Fight Against Malaria project will use AutoDock 4.2 and the new AutoDock Vina computer software to evaluate how well each candidate compound (molecule) attaches ("docks" or "binds") against a malarial target (usually a protein molecule.) Millions of candidate compounds will be tested against 14 different molecular drug targets from the malaria parasite in order to discover new compounds that can block (inhibit) the activity of these multi-drug-resistant mutant superbugs. These candidates will be tested by docking flexible models of them against 3-D, atomic-scale models of different protein drug targets from the malaria parasite, to predict (a) how tightly these compounds might be able to bind, (b) where these compounds prefer to bind on the molecular target, and © what specific interactions are formed between the candidate and the drug target. In other words, these calculations will be used to predict the affinity/potency of the compound, the location where it binds on the protein molecule, and the mode it uses to potentially disable the target. Compounds that can bind tightly to the right regions of particular proteins from the malaria parasite have the potential to "gum up" the parasite's machinery and, thus, help advance the discovery of new types of drugs to cure malaria. Since these predictions are not perfectly accurate, the top-ranked candidate compounds discovered in these virtual experiments will then be tested in "biological assays" performed by research collaborators in test tubes and Petri dishes.

Once the collaborators have proven that some of these candidate compounds are definitely able to help eliminate the malaria parasite, then The Scripps Research Institute and other researchers throughout the world can try to optimize these promising compounds to increase their potency against the target while decreasing their ability to bind to human proteins (since binding to certain human proteins causes toxic side effects). Once it is known that a compound is a novel inhibitor of one of these drug targets, "medicinal chemists" can then extend and modify these compounds in order to accelerate the development of new anti-malaria drugs.

This project will use two different types of "docking" programs to search for new compounds that can bind to and block the activity of protein drug targets from the malaria parasite. Both of these docking programs were created and developed by the Olson lab at The Scripps Research Institute. The first phase of the project will computationally evaluate the potential potency of millions of compounds using the new software AutoDock Vina. The second phase of the project will computationally re-evaluate the potency of the same compounds using the program AutoDock4.2. These two different types of docking programs each use different algorithms when searching for the location where a compound binds and when predicting the detailed mode it uses to bind to that location of the protein target, and they both use different "scoring functions" to evaluate the potency of the binding mode they predicted. Since no computational tools are perfectly accurate, harvesting compounds that score well with multiple different types of computational tools can increase the probability of discovering promising new compounds. In the Olson lab's experience with the FightAIDS@Home project (see Volume 10), evaluating compounds with both AutoDock and Vina facilitated the discovery of novel inhibitors of HIV protease (which is a notoriously difficult protein to target).

Both AutoDock Vina and AutoDock4.2 will be used to screen millions of candidate compounds against 14 different "validated drug targets" and "potential drug targets" from the malaria parasite. Basically, these experiments will target every relevant protein from the malaria parasite that has an atomically-detailed 3-D structure available. GO Fight Against Malaria will screen candidate compounds against the following protein targets from the malaria parasite: dihydrofolate reductase, enoyl-acyl-carrier-protein reductase (also known as Fab I), purine phosphoribosyltransferase, purine nucleotide phosphorylase, M1 neutral aminopeptidase, falcipain (a cysteine protease), glutathione reductase, glutathione S-transferase, dihydroorotate dehydrogenase, orotidine 5'-phosphate decarboxylase, merozoite surface protein-1, profilin, 3-oxoacyl acyl-carrier-protein reductase (also known as Fab G), and beta-hydroxyacyl-acyl-carrier-protein dehydrase (also known as Fab A/Z).

Using World Community Grid to run the GO Fight Against Malaria project will greatly accelerate these experiments and will also enable very ambitious research goals that would not be feasible without it. Screening millions of compounds against at least 14 different malaria targets using two different docking programs would take far more resources and time than academic researchers can obtain or spend. What can be accomplished with one (1) year of calculations on World Community Grid could take at least one hundred (100) years to complete using the resources normally available to the researchers at The Scripps Research Institute. Without the tremendous resources provided by World Community Grid, the project goals would have to be significantly scaled back to only screening a few thousand compounds against a few of these different malaria targets using a single docking program. World Community Grid will expand this malaria research by at least three orders of magnitude, greatly accelerating the rate at which these computational results can be obtained.

All GO Fight Against Malaria results will be in the public domain in the form of the virtual screening data that will be generated on World Community Grid and will be freely available to the global community of malaria researchers. Consequently, many other labs throughout the world will be able to use these results to help them discover new anti-malaria compounds that they and The Scripps Research Institute can then develop into new classes of drugs to treat this severe and neglected disease.

Research Participants
The researchers involved in the Global Online Fight Against Malaria project work at The Scripps Research Institute (TSRI) in La Jolla, California, U.S.A. Professor Art Olson, of the Molecular Graphics Laboratory at TSRI, is the Principal Investigator (P.I.) for this project.

The Global Online Fight Against Malaria (or "GO Fight Against Malaria") team includes:

* Professor Arthur J. Olson, The Scripps Research Institute, La Jolla, CA, U.S.A.
* Alex L. Perryman, Ph.D., The Scripps Research Institute, La Jolla, CA, U.S.A.
* Stefano Forli, Ph.D., The Scripps Research Institute, La Jolla, CA, U.S.A.
* Sargis Dallakyan, Ph.D., The Scripps Research Institute, La Jolla, CA, U.S.A.
* Ruth Huey, Ph.D., The Scripps Research Institute, La Jolla, CA, U.S.A.
* Mike Pique, The Scripps Research Institute, La Jolla, CA, U.S.A.
* Associate Professor of Medicinal Chemistry Subhash Sinha, The Scripps Research Institute, La Jolla, CA, U.S.A.


Technical Consultants and Collaborators:

* Associate Professor and Associate Research Fellow Jung-Hsin Lin, School of Pharmacy, National Taiwan University, Taipei, Taiwan, and Division of Mechanics, Research Center for Applied Sciences, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
* Professor John H. Elder, The Scripps Research Institute, La Jolla, CA, U.S.A.
* Associate Professor Bruce Torbett, The Scripps Research Institute, La Jolla, CA, U.S.A.
* Garrett M. Morris, D. Phil., InhibOx, Ltd., Oxford, UK
* Gira Bhabha, Ph.D., The Scripps Research Institute, La Jolla, CA, U.S.A.

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График работы проекта
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Sonechko
Dec 31 2012, 13:35
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Встиг Сапфір до НР добити, думав ще чисту енергію, але провтикав з налаштуваннями і 60 днів перерахував інший проект, ех...) ну але в новому році вже всі дорахую активні проекти) drinks2.gif

п.с. ПОмітив що Емеральдовий глобус зараз, круть)))


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Rilian
Feb 9 2013, 14:24
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http://gofightagainstmalaria.scripps.edu/i...l-malaria-drugs

новые графики и результаты работы проекта


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Rilian
Feb 12 2013, 13:00
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Кранчер заметил ошибку в публикации проекта smile.gif

http://www.worldcommunitygrid.org/forums/w...offset,0#412087

командная работа smile.gif koc.gif

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еще новый апдейт о состоянии проекта
(% completion statistics from February 7, 2013)

http://gofightagainstmalaria.scripps.edu/i...l-malaria-drugs


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Rilian
May 23 2013, 22:13
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Внезапно, этот проект тоже завершается

вот статус апдейт за 22 мая 2013

I just submitted the last batch for phase 1 of GFAM to the IBM World Community Grid team. The final batch # = 116485. After that batch (and all the ones before it) have finished crunching, the GFAM project will go on a long pause. But whenever we make a new discovery in the GFAM results and then publish a paper on it, I will post the news here and on the GFAM site, to keep you all informed about the progress that you helped us achieve.

See:
http://gofightagainstmalaria.scripps.edu/i...l-malaria-drugs

Thank you very much for your continued support!

Cheers,
Alex L. Perryman, Ph.D.

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Осталось 15 дней до конца этой фазы проекта!


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MAGADAN
May 24 2013, 08:03
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Парк из ОДНОГО ПиСиБотА Разбежалась ферма :(



Прям кошмар какойто smile.gif
Я хотел добраться спокойно до 2-х лет а теперь и год могу неуспеть sad.gif
Тоже самое и по HPF 2 sad.gif

А в общем все замечательно что проекты приходят к своему логическому завершению


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Я видел такое, что вам людям и не снилось!
Атакующие корабли,пылающие над Орионом!
Лучи СИ , разрезающие мрак у ворот Тангейзера!
Все эти мгновения затеряются во времени,как слёзы в дожде!
Пришло врёмя умирать!


Мне жаль небосвод этот синий,
Жаль землю и жизни осколки,
Мне страшно,что сытые свиньи,
Страшней,чем голодные волки.

История МОИХ побед :
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Rilian
May 25 2013, 13:27
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10 days of new work remaining for GFAM

Based on current estimates, there are now approximately 10 days of new work remaining for the GFAM project. Once all new work has been sent out for the project, only resend work units will be available (work units not previously computed correctly or on time). The last new work unit for GFAM will be GFAM_x3LLT_PfLammer_w5WATs_0116485_0103.

Thank you to all who have donated their CPU time to this project.

Seippel

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MAGADAN, запасай задания в кэш на 10 дней.. Подключай друзей...


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Rilian
May 28 2013, 23:05
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6 дней до завершенія видачі заданій! Кому надо бейджик, запасайте кэш!


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Rilian
Jun 4 2013, 10:55
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Выдача новых заданий закончена. Выдаются только задания для перепроверки. Если кто охотится за медалью тут, запасайте очень большой кэш

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Rilian
Jun 14 2013, 13:42
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большое научное обновление о планах, проблемах и успехах проекта

кратко:

1) заканчивается первая фаза проекта. Вместо запланированных 12Млн комбинаций обработано 1100М то есть в 100 раз больше !
2) малярийный плазмодий мутирует и существующие лекарства с этим скоро перестанут справляться. Это природа, детка! Половина населения Земли в группе риска.
3) нужны абсолютно новые подходы к противодействию мутантов
4) следующие несколько лет планируется изучать полученные результаты
5) в результате 1 фазы проекта идентифицировано несколько десятков потенциальных ингибиторов ключевых участков плазмодия

To the members of World Community Grid:

As we finish the first phase of the GO Fight Against Malaria project (“GO FAM”), we are very grateful for all of the computer power you donated to us, for all of the interest you have displayed, and for all of the support you have given us. Plasmodium falciparum (the species of parasite that causes the deadliest form of malaria) kills more people than any other parasite on the planet. Almost half of the entire human population is at risk of being infected with malaria. Although there are several currently-administered drugs that work well against many strains of malaria, treating patients with those drugs eventually spurs the evolution of new multi-drug-resistant mutant “superbugs” against which the drugs stop working well. It's just the nature of nature: the presence of the different anti-malaria drugs within the human hosts causes the selection of new mutant strains of malaria that can escape the effects of the drugs. Consequently, scientists like us need to keep searching for new types of drugs that will work against these mutant superbugs that constantly evolve and spread. In the Olson lab, we are also trying to advance the discovery and design of new types of drugs that can be used in new combination therapies that should make it more difficult for the parasite to evolve new types of drug-resistant mutants.

In the experiments we performed for the GO Fight Against Malaria project, we screened 5.6 million commercially-available compounds against several different models of 22 different classes of well-validated and potential drug targets. Our goal is to find new “hits” against these targets. Hits are compounds that have some inhibitory effect on the biological activity of one of these targets. But finding a hit is only the beginning of the process (a complicated process that can take several years to a couple of decades to complete). Scientists from around the world called “medicinal chemists” can then work with structure-based computational chemists like us to try to increase the potency and decrease the potential toxic side effects of these compounds, which involves processes called “hit-to-lead development” and then “lead optimization”. Leads are larger, more structurally complex, potential drug candidates that generally display nano-Molar potency (that is, they are around 1,000 times more potent than “hits,” which means that only a small amount of a lead compound is required to affect the activity of the target). Your generous support enabled us to generate a massive amount of data that is already helping us discover new hits that should help advance the fight against malaria. Thank you very much for donating your unused computer time to this project and to the other projects on World Community Grid! This community has truly felt like a global on-line family.

This is not the end of our malaria research―it is just the end of “phase 1” of the GO FAM calculations on World Community Grid. During the next few years, we will continue to process, measure, and analyze the results of the virtual screens we have already performed on GO Fight Against Malaria. We will extend the collaboration that we started with Professor Mike Blackman's lab in the Division of Parasitology at the Medical Research Council's (or “MRC's”) National Institute for Medical Research (or “NIMR”), in London, UK, and with InhibOx, Ltd., on the potential drug target “PfSUB1” (see target class #6 on http://gofightagainstmalaria.scripps.edu/i...l-malaria-drugs ). The Blackman lab and InhibOx both shared the homology models that they had created of the potential structure of PfSUB1, which allowed us to begin screening compounds against putative structures of this target. When malaria parasites replicate themselves inside a red blood cell, the “daughter” parasites eventually rupture the infected host cell, which allows the new parasites to escape and then invade and infect other red blood cells. The subtilisin-like serine proteases from Plasmodium falciparum (also known as PfSUB1) are involved in this ability of the malaria parasites to escape (or “egress”) an infected red blood cell. The Blackman lab has shown that the PfSUB1 enzymes have an additional role in “priming” the merozoite stage of the parasite prior to its invasion of red blood cells. Thus, PfSUB1 is involved in both the egress and the infection process. Of critical importance, when the Blackman lab solved the first crystal structure of PfSUB1 (that is, the atomically-detailed, 3-D map of where all its atoms are), they shared that unpublished structure with us, which allowed us to perform new virtual screens against PfSUB1 that should be more accurate (that is, more accurate than just screening against “homology models”). In the results of GO FAM Experiment 27, we already discovered the first “small molecule” inhibitor of PfSUB1 ever identified, and it displayed a proper “dose-response curve” (that is, at higher concentrations of the inhibitor, it shuts down the activity of PfSUB1 more and more effectively, which indicates that it is likely a “specific” inhibitor). This compound, nicknamed “GF13”, is a fairly weak inhibitor, but we're working with InhibOx and with the Blackman lab to find more potent compounds. InhibOx used some of the software that they created to search for other compounds that have similar electronic signatures to GF13 (specifically, they calculated which NCI compounds had “ECFP fingerprints” similar to GF13). We then searched the ZINC server ( http://zinc.docking.org ) to find compounds that had some structural similarity to those compounds that InhibOx identified, and we created a new “focused library” of similar compounds for a subsequent virtual screen that we performed on the Linux cluster at TSRI. In that new screen we identified a set of ~ 20 new compounds that have some structural similarity to GF13, and the Blackman lab will test their effectiveness soon. Discovering a more potent inhibitor of PfSUB1 should help us prove whether this malarial enzyme is a valid drug target or not. If it is, then this line of research will also help us advance the ability to cure and potentially prevent malaria infections. After the next round of experimental tests have been finished, we will start writing a paper on these results. When it finishes the normal peer-review process, we will definitely share the published version with all of you.

We will also continue the collaboration we developed with Professor Peter J. Tonge's lab. Professor Tonge is the Director of Infectious Disease Research at the Institute for Chemical Biology and Drug Discovery at Stony Brook University in NY. He has been a leading expert in the battle against extremely-drug-resistant tuberculosis infections, and his lab has helped us by testing our candidate compounds against the valid drug target called “InhA,” which is an enoyl-ACP reductase (or “ENR”) from Mycobacterium tuberculosis (the deadliest bacteria on Earth). The enoyl-acyl-carrier-protein reductase (or “ENR,” which is also called Fab I) is part of a unique metabolic pathway in the apicoplast (that is, it's an enzyme that is part of a metabolic pathway that is not present in humans, which should hopefully decrease the toxic side effects of ENR inhibitors). Specifically, ENR is part of a Fatty Acid Synthesis pathway (called “FAS II”) that human cells do not have. The version of ENR from malaria is just called Pf ENR, while the version from Mycobacterium tuberculosis is called “InhA”. One of the main drugs used to treat tuberculosis is called isoniazid (or “INH”), and it kills that deadly bacteria by shutting down the activity of InhA. But drug-resistant mutants against which isoniazid loses its effectiveness keep evolving and spreading, which is why we are searching for new inhibitors of InhA. In addition, we included InhA in the GO FAM experiments (see target class #2 at http://gofightagainstmalaria.scripps.edu/i...l-malaria-drugs ), because it is structurally similar to the ENR enzyme from Plasmodium falciparum (the parasite that causes the deadliest form of malaria), and because some inhibitors of InhA also block the activity of the ENR target from malaria. By advancing the research against InhA, we should be able to simultaneously help advance the research against both extremely-drug-resistant tuberculosis and against multi-drug-resistant malaria. In the results of GO FAM Experiment 5, we identified 19 candidate compounds as potential inhibitors. Of the 16 soluble compounds, 8 candidates (at a 100 micro-Molar concentration) shut down InhA activity by ~ 30% or more, and the most potent inhibitor we discovered displayed an IC50 value of ~ 40 micro-Molar (which means that when the compound is present at a 40 micro-Molar concentration, it inhibits InhA activity by 50%). Finding a new low micro-Molar inhibitor of InhA is a significant achievement (and so is having a hit rate of 8/19 candidates from a virtual screen), but we will still need to optimize the compound and make it at least a thousand times more potent before it becomes a drug-like candidate called a “lead.” These virtual screens on GO FAM (and, thus, the new inhibitors we discovered) were designed to target one of the main mechanisms that Mycobacterium tuberculosis has evolved in order to resist the effects of drug treatment with isoniazid. After the Tonge lab characterizes these compounds in more detail, we will start writing a paper on these exciting new results, too. When that paper completes the normal peer-review process, we will share the published version with all of you. And we will continue to extend this promising line of research against tuberculosis and malaria.

Some World Community Grid members have asked on the Forum whether “phase 1” of GO FAM ended prematurely. In fact, the first phase of GO FAM was substantially larger than we had initially planned. In the proposal to create this GO FAM project, we originally planned to screen 2.4 million compounds against 5 different sites on 2 drug targets and then to screen 20,200 compounds against 11 other malarial targets, for an initial estimate of 12.4 million different docking jobs. When phase 1 of GO FAM finishes in the next few days, we will have completed screening ~ 5.6 million compounds against 204 models of 22 different classes of malarial targets, for a total of over 1.16 billion different docking jobs with the “AutoDock Vina” software. Thus, phase 1 included over 1.1 billion more docking jobs than we had initially planned or proposed. If we didn't have the massive resources provided by World Community Grid, it would have likely taken us many decades to over a hundred years (using the speed of current computers) to generate this many virtual screening results (which means that it would not have been feasible to even try to tackle a goal this ambitious; we would have had to scale back the project's goals substantially and only screen a few thousands compounds against only a couple classes of targets). It will take us a few years to: (1) process, measure, and analyze these results; (2) to form and extend collaborations with experimental labs that can help us test and refine these predictions; (3) to write and publish papers on these experiments; and (4) to obtain grant funding. We have to obtain grant funding before we can come back and start “phase 2” of the GO FAM project, since we need to be able to pay for personnel and for the compounds that need to be assayed, and we need to help pay for the costs of those assays that our collaborators will perform. But we need to publish some papers on this research first, in order to increase our chances of being able to get grant funding. It's a long-term, complicated, and uncertain process, but we will be persistent. We hope to eventually start “phase 2” of GO FAM, but it will take a few years before we will know anything for sure. In the meantime, we will keep processing, measuring, and analyzing the results from phase 1, we will keep advancing our collaborations and trying to start new collaborations, and we will keep sharing our progress with you on the GO FAM site and on the Forum at World Community Grid. Please be patient, and we'll keep advancing the fight against superbugs of malaria and tuberculosis.

The GO FAM team thanks you all for your help and generous support!!!

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Rilian
Aug 17 2013, 10:24
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