FightAIDS@Home News

November 29th, 2006 Volume 2

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’d like to give an update on our work, and the research direc-tions that we are planning. Recent news in-dicates 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 mile-stones. Our work is not finished, but we are greatly en-couraged 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 ex-periment, screening a large library of

diverse chemical compounds against a panel of “wild-type” and mu-

tant HIV proteases, a major target of AIDS therapy. We

called this “Stage 1”. That terminology implied a sequential process that is not precisely how

our experiments pro-ceed. In fact, like most researchers, we run sev-eral 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.

Our first experiment finished running on the Grid last April. In that work, Experiment 1a, we screened

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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 fash-ion, 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 col-laborators have run assays of these compounds against wild type and several mutant proteases. About 5 of the 40 compounds show interesting activ-ity in inhibiting the proteases. This work is continu-ing to see if any of these compounds show extraordi-nary promise.

In the meantime, we are pursuing more sophisticated analyses of the results of Experiment 1. This work takes several forms. A deeper analy-

sis 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 impor-tant 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 re-sources 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 rele-vant 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 dif-ferent 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 im-proved 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

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A plot showing the predicted binding energy of the top-scoring ligands versus the various HIV Proteases from x-ray crystallo-graphic experiments. The band of blue, green and yellow colors along the top are the clinically-approved protease inhibitors.

inhibitor can be flexible and change shape as they interact.

Experiment 4 involves looking for HIV protease in-hibitors 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 identi-cal 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 con-served, 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 ex-perimental 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 impor-tantly, your involvement in our attempts to develop better AIDS treatments and novel drug-development methodologies is greatly appreciated.

Prof. Arthur J. OlsonDr. Garrett M. Morris

Dr. William LindstromAlexandre Gillet

Dr. Richard K. BelewMax W. Chang

References1. Brik, A., et al., 1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors. Chem-biochem, 2005. 6(7): p. 1167-9.

2. Heaslet, H., et al., Structural Insights into the Mecha-nisms 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.

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