From WCG: “GO Fight Against Malaria update: promising early findings for malaria & drug-resistant tuberculosis”

14 Jul 2014
Dr. Alexander L. Perryman

Summary
Dr. Alexander Perryman describes the analysis and initial findings from the first phase of GO Fight Against Malaria, which include the discovery of several promising hits against key drug targets for treating both malaria and drug-resistant strains of tuberculosis. They are conducting further analysis and experimentation on the massive amount of data generated by World Community Grid volunteers.

Dear fellow volunteers of World Community Grid,

In under two years, World Community Grid volunteers performed the world’s largest docking project, carrying out over 1 billion calculations to help us identify chemical compounds to advance the treatment of increasingly drug-resistant strains of malaria and other diseases – a process that would have taken over a hundred years on the type of computer clusters currently available at most universities.

Since we completed GO Fight Against Malaria (GFAM) calculations on World Community Grid a year ago, we’ve been analyzing the generated data. Although that process will continue for some time still, early analysis has revealed several promising findings.

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First, we identified the first “œsmall molecule” inhibitor (i.e., drug-like compound) to block the activity of a particular malaria enzyme involved in infection, the first step in developing a potential treatment or prevention aimed at this malaria drug target.

Also, a subset of your calculations was conducted against a drug target for malaria which shares a similar atomic structure to a Mycobacterium tuberculosis enzyme. With extensively drug-resistant strains of tuberculosis on the rise, there is a pressing need to identify more effective treatments. We therefore included this particular tuberculosis drug target in our GFAM experiments. In doing so, we have identified several chemical compounds as potential inhibitors of this enzyme and have confirmed these results with initial laboratory tests. A very impressive number of the promising chemical compounds identified through the virtual screenings you computed on World Community Grid have gone on to perform well in additional lab testing: 20% were “hits”, vs. less than 1% on average for other experimental (“œwet lab”) high-throughput tuberculosis experiments.

We are now designing and synthesizing new derivatives of these inhibitors to further refine them as viable drug candidates. Read on for more details about this early analysis work, and we’ll be able to share more information once we publish our findings. In the meantime, I want to thank GFAM volunteers for allowing us to advance this important and often neglected area of research.

Largest set of computational docking experiments ever performed

GFAM was launched on IBM’s World Community Grid on November 16, 2011. Malaria is one of the three deadliest infectious diseases on Earth (the other two are HIV and tuberculosis). Plasmodium falciparum (Pfal, or Pf), the species that causes the worst form of malaria, kills more people than any other parasite on the planet. Over 200,000,000 clinical cases of malaria occur each year, and over one million people are killed by malaria every year. Over three billion people (almost half of all humans) are at risk of becoming infected with malaria, and every 30 seconds, another child dies of malaria.

GFAM ran on World Community Grid for 19 months, during which the tremendous computational power provided by World Community Grid volunteers like you helped us generate massive data sets against 22 different types of drug targets, to seed the discovery of new drugs to treat malaria. We performed “docking calculations,” which explore how well different “small molecules” (pieces of drug-like compounds) are able to bind and potentially block the activity of critical pieces of the molecular machinery that the pathogens use to survive, replicate, and spread throughout humanity. Docking calculations use flexible models of these small molecules to explore the energetic landscape of atomic-scale models (on the scale of 0.0000000001 meters) of proteins that perform critical functions for the parasite’™s lifecycle and infection process. These calculations predict how tightly a compound might bind to the target (that is, how potent it might be), where the compound probably prefers to bind, and what specific types of interactions might be formed between the compound and the drug target. One docking calculation refers to the process of docking a flexible model of a single compound against one particular version of one target. In this first phase of GFAM, World Community Grid volunteers performed 1.16 billion different docking calculations that explored the potential activity of 5.6 million different compounds against drug targets from malaria (and against some targets for treating drug-resistant tuberculosis, Methicillin-Resistant Staphylococcus aureus (MRSA), filariasis, and bubonic plague, when the targets from those other pathogens had structural similarity to the targets from malaria). With the computing power that you generously donated, GFAM was the first project to ever perform a billion different docking calculations. Performing this many calculations could have taken over a hundred years on the type of computer clusters currently available at most universities. We could not have accomplished this feat without your help. We are also grateful for the $50,000 in seed funding provided by the IBM International Foundation, from part of the prize money that IBM’s computer Watson won on Jeopardy!™. Thus far, that seed money has been the only funding that the project has received, but we are currently writing grants that focus on analyzing and extending the GFAM data.

Finding a “œhit” that inhibits a critical protein involved in malaria infections

“Hits” are compounds that have some inhibitory effect on the biological activity of one of these drug 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 “œlead optimization”. “œLeads” are larger, more structurally complex, potential drug candidates that generally display nanomolar potency (that is, they are around 1,000 times more potent than “œhits”, which means that only a tiny amount of a leading compound is required to affect the activity of the target). In collaboration 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 “œNIMR”), in London, UK, and with InhibOx, Ltd, we searched for the first small molecule inhibitors of the potential drug target “œPfSUB1″ (see target class #6 on http://gofightagainstmalaria.scripps.edu/index.php/how-we-will-discover-potential-malaria-drugs). When the Blackman lab solved the first crystal structure of PfSUB1 (that is, the atomically-detailed, 3-D map of where all of its atoms are), they shared that unpublished structure with us, which allowed us to perform virtual screens against PfSUB1. These virtual screens are searching for “small molecule” inhibitors (that is, compounds with some similarity to pieces of known drugs) that can block the activity of this malarial enzyme. 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 “œegress”) an infected red blood cell. The Blackman lab has shown that the PfSUB1 enzyme has an additional role in “priming” the merozoite stage of the parasite prior to its invasion of red blood cells (in other words, it is involved in processing certain other malarial proteins in order to prepare and activate them, so that the parasite can invade our blood cells). Thus, PfSUB1 is involved in both the egress and the infection process. In the results of GFAM Experiment 27, we 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 “œspecific” inhibitor, instead of a non-specific compound that randomly happens to impede activity a bit for many different types of proteins (but this will have be tested against other types of proteins to know for sure). This compound, nicknamed “GF13”, is a fairly weak inhibitor: at a 200 micromolar concentration, it blocks activity of PfSUB1 50%. Strong hits will block 50% of the target’s activity in the 1 to 50 micromolar range (the smaller the # of micromoles per liter that are needed to shut down activity, the more potent a compound is).

See the full article here.

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