From FAAH at WCG: “Teamwork yields experimental support for FightAIDS@Home calculations”

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By: The FightAIDS@Home research team
6 Nov 2014

Imaging studies have now confirmed some of the computational predictions made during FightAIDS@Home, providing important confirmation of our methodology and the value of your computational results. This work is ongoing, but promises to increase our understanding of how HIV protease can be disrupted.

The “exo-site” discovered in HIV protease (shown here in green), showing the original bound 4d9 fragment (shown here as red and orange sticks) and the volume (shown as the orange mesh) that is being targeted by FightAIDS@Home. (image credit: Stefano Forli, TSRI)

Our lab at the Scripps Research Institute, La Jolla, is part of the HIV Interaction and Viral Evolution (HIVE) Center – a group of investigators with expertise in HIV crystallography, virology, molecular biology, biochemistry, synthetic chemistry and computational biology. This means that we have world-class resources available to verify and build upon our computational work, including the nuclear magnetic resonance (NMR) facility at the Scripps Research Institute, Florida. NMR is a technique for determining the molecular structure of a chemical sample, and therefore is very useful for validating some of the predictions made during the computational phase of FightAIDS@Home.

We’re excited to announce that our collaborators at Scripps Florida have now optimized their NMR experiments and have been able to characterize the binding of promising ligands with the prospective allosteric sites on the HIV protease. These sites represent new footholds in the search for therapies that defeat viral drug resistance. The NMR experiment allows us to detect the location of the interactions between the candidate inhibitors and the protein, but unlike X-ray crystallography experiments, these interactions are measured in solution, which better represents the biological environment.

In fact, the first results from the NMR experiments validated the exo site we so thoroughly investigated in FightAIDS@Home. As a result, we now have experimental evidence that a small molecule binds to the exo site in solution with structural effects that seem to perturb the dynamic behavior of protease, even with a known inhibitor in the active site.

There are many more NMR experiments still to run, but another advantage of NMR over crystallography is that it does not require the lengthy step of growing diffraction-quality crystals. This allows higher experimental throughput, so we look forward to experimental confirmation of many more compounds in much shorter time. So far we have shipped 15 compounds to test and another batch is going to be sent this week. The new compounds will help to validate another potential interaction site on one of HIV protease’s two movable “flaps”.

Once the validation is completed, we will proceed to test a number of compounds that we identified in different FightAIDS@Home experiments for all of the target protease allosteric sites.

As always, thank you for your support! This research would not be possible without your valuable computing time.

The Scripps research team needs your help to continue making progress on developing new treatments for AIDS! Take part in our decade of discovery competition by encouraging your friends to sign up to World Community Grid today to start donating their computer or mobile device’s computing power to FightAIDS@Home. There’s just over a week left and some great prizes are up for grabs – get started today!

Here’s to another decade of discovery.

See the full article here.

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