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What's new about Phase 2 of the FightAIDS@Home project? What will this phase of the project do?

Phase 2 of the project takes results from the molecular docking approach used in Phase 1 and produces a re-evaluation of the top hits found from the virtual screening, to further narrow down potential drug candidates.

While Phase 1 conducted virtual screening of chemical libraries using AutoDock and AutoDock Vina software tools, Phase 2 introduces a completely new computational method into the FightAIDS@Home effort: the BEDAM technique, implemented with Academic IMPACT software, a molecular simulation tool. Academic IMPACT models the thermodynamics of binding of a ligand to a protein including the reorganizational free energy of the docked complex. Much more computer time is needed to evaluate each docked complex, so only the top candidates from Phase 1's virtual screen are examined in this way.

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What benefits do you anticipate from this phase of the project?

The goal of the FightAIDS@Home project is to find new leads for HIV therapeutics. It is the first step in a long pipeline that may eventually lead to a new drug or therapeutic strategy. Subsequent to virtual screening in Phase 1 and further analysis in Phase 2 for hit identification, the compounds identified must be either purchased or synthesized to be tested experimentally. This is an expensive process, so if our list of hit compounds contains a large number of false positives, much time and money will be wasted. With the BEDAM post-processing of the virtual screening results, we can eliminate much of the false positive results from Phase 1 and save time and money in moving the drug candidates into the drug development pipeline.

Also, the methods that we use on HIV drug discovery are generic and can be applied to any other disease target. This means that other drug search projects on World Community Grid should benefit from our implementation of this computational pipeline.

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How does Phase 2 relate to Phase 1?

Phase 2 further refines the results from Phase 1 and helps us identify "false positives," thus saving time and money in future drug development processes.

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Are there plans to continue work on Phase 1 simultaneously?

Yes, we plan to continue to do virtual screens of large chemical libraries against a number of HIV targets. As the biology of the HIV life-cycle continues to be researched by the HIVE Center, and other efforts around the world, new targets and variations of existing targets are discovered and can be used in our Phase 1 activities. We are still currently screening many variations and sites from HIV Protease, Integrase and Reverse Transcriptase.

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How does this phase of the project build on the progress already made with FightAIDS@Home?

Significant new aspects of the biology of HIV have been discovered over the past 10 years. The research team's work on HIV protease has discovered new sites on the protein that represent targets that may result in new classes of drugs. Their work on HIV Integrase is exploring new chemical compounds that target a newly discovered mechanism to inhibit HIV infectivity. Again, this work may result in a new class of drugs that will work to defeat the virus and its ability to evolve drug resistance. The BEDAM approach being used in Phase 2 will help move us closer to the discovery of such drugs.

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What is BEDAM and how has it been used in the past?

BEDAM stands for “Binding Energy Distribution Analysis Method”. It is a method developed by the Levy group which uses advanced sampling and analysis techniques to calculate absolute binding free energies based on a foundation in statistical mechanics and data generated from molecular dynamics simulations.

In a collaboration between the Olson group at The Scripps Research Institute and the Levy group at Temple University, BEDAM techniques were recently developed and used in a computational challenge (SAMPL4) demonstrating that docking coupled with subsequent BEDAM processing gives more reliable hits. This challenge used blind data from a pharmaceutical company working on HIV Integrase inhibitors. The AutoDock Vina/BEDAM modeling performed the best among all automated computational predictions submitted in the challenge.

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Why is the BEDAM method useful to FightAIDS@Home? How is it different from other approaches previously used on the project?

The BEDAM approach uses Academic IMPACT, a computer program developed in the Levy Lab at Temple University to model the thermodynamics of protein-ligand binding. It is not a docking tool, but rather a method to evaluate the energetic and entropic components of the complexes from the molecular interactions predicted by docking. It would take prohibitively long to use the BEDAM approach for the millions of compounds without screening them first using the much faster docking software first, as done in Phase 1. Since the energetic estimates from the docking calculations are approximate -- to allow the high throughput needed to screen millions of compounds -- there are many so-called "false positives" in the list of top ligand protein complexes. The BEDAM analysis has been shown to potentially eliminate many of these false positive hits.

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