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/inde...r-potential-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/inde...r-potential-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!!!