andidates from grid-based research are really no different to leads that have entered the pipeline through more conventional paths. They will still require significant medicinal chemistry effort to be developed into drug candidates. However, he says, the greater number of grid-generated leads does mean an increased probability that at least one will become an approved treatment.
Modelling limitations aside, Jurisica believes that computation is going to 'revolutionise' medicine. He points out that it was exactly this kind of 'brute force computing' that enabled the identification of thousands of prognostic signatures in lung cancer. Indeed, this success has led to Jurisica's team preparing a new WCG proposal where the main idea is to combine the knowledge of physical protein interactions, protein disorder and other properties with failed crystallisations to predict co-crystallisation experiments.
Tackling the hardest problems
Watowich points out that drug discovery projects for any number of neglected, rare and infectious diseases are effectively endless. 'The computing power of the World Community Grid will allow researchers to think beyond the confines of traditional computing and launch large computing efforts that accurately model physical processes.' He adds that 'the relatively low cost of the WCG makes it ideal for studying diseases that do not appear to offer an attractive return on investment to large pharmaceutical companies'.
Not only is the WCG an 'incredible resource' for researchers who may have no other means to test their ideas, notes Jasinski, it is also a starting block for attacking diseases that have been traditionally hard-placed to treat. One such disease is Aids. According to the Global Health Council, in 2008, 33.4 million people around the world were living with HIV and 2.7 million people were newly infected with the virus. While the disease can be treated with drugs, there is no cure. But perhaps more problematic, is that the virus, often called a 'sloppy copier', is constantly evolving new variants leading to drug resistance.
One grid project is modelling the binding of 300?000 potential HIV protease inhibitors
© PHANTATOMIX / SCIENCE PHOTO LIBRARY
Arthur Olson, from the Department of Molecular Biology at The Scripps Research Institute in La Jolla, US, is using the World Community Grid to address this issue. 'From a medical point of view, evolution of resistance in HIV infected patients is a major threat to their continued survival. Our approach is to understand the mechanisms of viral resistance and to develop therapeutics that can box the virus into a corner from which it cannot escape.' The team is screening more than 300,000 molecules against multiple variations of two target sites on the HIV protease, which is involved with virus maturation. 'Typically we hope to whittle this number down to 30 or 40 compounds that we can then order and hand on to our collaborators to test experimentally,' he says.
Wide open possibilities
The future of research using the WCG isn't just about seeing how proteins interact with other molecules. At New York University, US, Richard Bonneau is using the WCG to predict how proteins fold. Taking the collection of microbes found inside and on the skin of humans, the team is looking at whether proteins derived from the genes of these organisms - many of which have gene sequences not seen before - perform novel functions or if their resulting protein structure is similar to known structures. 'Using the WCG, we can start to answer some of these questions and maybe uncover new enzymes or protein scaffolds while trying to understand the full extent of protein fold space,' says Kevin Drew, a doctoral student in Bonneau's team. Normally, this would be a costly and time consuming exercise but the WCG can help push findings into the lab, he says. To date, proteins translated from more than 94 genomes have been folded in this project.
Indeed, genomes and DNA are expected to play an expanding role in future grid research. Already, Olson and his team are beginning to use patien