FightAIDS@Home News
 
From Computer to Test Tube...
We have completed our first experiments.  First results from FightAIDS@Home computations are now being tested in the laboratory.
As we approach World AIDS Day 2006, we would like to give an update on our work, and the research directions that we are planning. Recent news indicates that the AIDS pandemic is still very much with us, and in fact is growing again.  The problem of drug resistance has become even more critical, since vaccine development has yet to provide a route to prevention and spread.
We have been running FightAIDS@Home on The World Community Grid for almost one year now, and have reached several important milestones.  Our work is not finished, but we are greatly encouraged by the results that we are getting thanks to the help of our FightAIDS@Home members around the globe who have enabled this research.
As with all scientific research, we run experiments — only our experiments are run on computers.  When we started out a year ago, we began our first experiment, screening a large library of diverse chemical compounds against a panel of "wild-type" and mutant HIV proteases, a major target of AIDS therapy.  We called this "Stage 1a". That terminology implied a sequential process that is not precisely how our experiments proceed.  In fact, like most researchers, we run several experiments at the same time.  Thus we have decided to change how we describe our work on the World Community Grid to be in terms of the experiments that we are running.
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Our first experiment finished running on the Grid last April.  In that work, Experiment 1a, we screened about 2,000 diverse compounds from the National Institutes of Health NCI compound library against a panel of about 300 HIV protease structures derived from x-ray crystallography and from computational modeling.  The results of this huge computation (several quadrillion energy evaluations), are now in hand, and have been analyzed in a preliminary fashion, by searching for the compounds whose average binding energy was the best across the most protease variants.  We have now ordered and obtained the 40 top compounds from the NIH, and our wet lab collaborators have run assays of these compounds against wild type and several mutant proteases.  About 5 of the 40 compounds show interesting activity in inhibiting the proteases.  This work is continuing to see if any of these compounds show extraordinary promise.
In the meantime, we are pursuing more sophisticated analyses of the results of Experiment 1.  This work takes several forms.  A deeper analysis of the statistics of our dockings may result in other promising compounds that we did not detect in our first pass. Additionally, an analysis of the relationships between the strength of a compound docking and the kinds of drug-resistant mutant proteases that it docks to, may reveal important information about the relationship between the inhibitor and the mechanism of resistance.  Also, the results of this first experiment are giving us valuable data on the reliability of our computational methods, and on the modeled structures that were included in our protease panel.  We are using this data to improve our models and our algorithms.
While this analysis is being carried out, we are running three more experiments on the World Community Grid.  Experiment 1b is an in depth look at the entire NCI compound library, which contains over 250,000 compounds.  This is needed to determine if the original diversity library is complete enough to represent the much larger set of compounds.  Even with the computational resources that our volunteers are providing, we cannot scan all possible mutants with these compounds, so we are picking only a few (wild type and some relevant mutants) to see if we uncover new compounds that are not in the diversity set.  So far, we have completed the screening of the entire library against the wild-type protease.
Similarly in Experiment 2 we have looked at a different compound library containing over 500,000 distinct chemical compounds. We have completed screening this library against a wild-type protease.  Narrowing down this library to those compounds that have reasonable activity against wild type, we will then screen those promising compounds against the panel of mutants.
Experiment 3 is a test of an improved method for our AutoDock code, where we allow some motion in the protease receptor as well as the ligand.  This is an important step in increasing the accuracy of the resulting docking predictions, since both the protein receptor and the inhibitor can be flexible and change shape as they interact.
Experiment 4 involves looking for HIV protease inhibitors that work by a totally different mechanism than existing drugs.  For this, we are screening the NCI library against the HIV protease monomer.  Since HIV protease functions only when two identical chains of the protein come together, if we can prevent the chains (each one is termed a "monomer") from joining, we can disrupt its function.  The parts of the monomer that are involved in the interface joining the two chains appears to be highly conserved, so if we can disrupt this interface with a drug, it may deter resistance by mutation. So far we have run about 50,000 dockings of the diversity set against 22 different monomer structures.
As we combine our computational results with experimental validation, our follow-on experiments will be to develop variations of the most promising compounds into libraries that we can screen against a panel of protease mutants.  In this on-going work we will also incorporate our improved methodologies into the computational procedures that we run.
There are now three scientific papers in preparation that are the direct result of the work that we have done on FightAIDS@Home.  Your contributions to this work are gratefully acknowledged.  More importantly, your involvement in our attempts to develop better AIDS treatments and novel drug-development methodologies is greatly appreciated.
Prof. Arthur J. Olson
Dr. Garrett M. Morris
Dr. William Lindstrom
Alexandre Gillet
Dr. Richard K. Belew
Max W. Chang
References
1. Brik, A., et al., 1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors. Chembiochem, 2005. 6(7): p. 1167-9.
2. Heaslet, H., et al., Structural Insights into the Mechanisms of Drug Resistance in HIV-1 Protease NL4-3. J Mol Biol, 2005.
3. Whiting et al. Inhibitors of HIV-1 Protease through In Situ Click Chemistry. Angewandte Chemie, 2005.
A plot showing the predicted binding energy of the top-scoring ligands versus the various HIV Proteases from x-ray crystallographic experiments.  The band of blue, green and yellow colors along the top are the clinically-approved protease inhibitors.