WCG FightAIDS@Home Phase 1

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WCG FightAIDS@Home Phase 1

Unread post by Alez » Tue May 09, 2017 5:26 pm

From WCG website

FightAIDS@Home

https://youtu.be/V6gzc8uUGJw


Project Status and Findings: The FightAIDS@Home project is the first World Community Grid project to run on Android smartphones and tablets. With the launch of the BOINC for Android app in July 2013, volunteer computing took a leap forward, starting with this project. Volunteers can now accelerate this critical research with their mobile devices. Learn more or start contributing now.

Also, the fight against AIDS recently got another boost when the World Community Grid team made a new modelling tool, developed by the Scripps researchers, available for the FightAIDS@Home project. This new tool, called Vina, is more accurate and significantly faster than the original tool, called AutoDock, when screening highly flexible compounds. However, AutoDock is more accurate in other experiments. The researchers can therefore pick the tool more appropriate for the task at hand.

Additional information about this project can be found on these pages, including the project's News & Updates page. You may also visit the researchers' FightAIDS@Home website, where you can find the latest status report. To discuss or ask questions about this project, please visit the FightAIDS@Home Forum.

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What is AIDS?
UNAIDS, the Joint United Nations Program on HIV/AIDS, estimated that in 2004 there were more than 40 million people around the world living with HIV, the Human Immunodeficiency Virus. The virus has affected the lives of men, women and children all over the world. Currently, there is no cure in sight, only treatment with a variety of drugs.

Prof. Arthur J. Olson's laboratory at The Scripps Research Institute (TSRI) is studying computational ways to design new anti-HIV drugs based on molecular structure. It has been demonstrated repeatedly that the function of a molecule — a substance made up of many atoms — is related to its three-dimensional shape. Olson's target is HIV protease ("pro-tee-ace"), a key molecular machine of the virus that when blocked stops the virus from maturing. These blockers, known as "protease inhibitors", are thus a way of avoiding the onset of AIDS and prolonging life. The Olson Laboratory is using computational methods to identify new candidate drugs that have the right shape and chemical characteristics to block HIV protease. This general approach is called "Structure-Based Drug Design", and according to the National Institutes of Health's National Institute of General Medical Sciences, it has already had a dramatic effect on the lives of people living with AIDS.

Even more challenging, HIV is a "sloppy copier," so it is constantly evolving new variants, some of which are resistant to current drugs. It is therefore vital that scientists continue their search for new and better drugs to combat this moving target.

Scientists are able to determine by experiment the shapes of a protein and of a drug separately, but not always for the two together. If scientists knew how a drug molecule fit inside the active site of its target protein, chemists could see how they could design even better drugs that would be more potent than existing drugs.

To address these challenges, the World Community Grid FightAIDS@Home project runs one of two software programs: one is called AutoDock, the other called AutoDock Vina (AD Vina), both developed in Prof. Olson's laboratory at The Scripps Research Institute. AutoDock is a suite of tools that predicts how small molecules, such as drug candidates, might bind or "dock" to a receptor of known 3D structure. The very first version of AutoDock was written in the Olson Laboratory in 1990 by Dr. David S. Goodsell, since then, newer versions, implemented by Dr. Garrett M. Morris, have been released which add new scientific understanding and strategies to AutoDock, making it computationally more robust, faster, and easier for other scientists to use. Until now, the FightAIDS@Home project ran its computations on the AutoDock software, but the researchers find that the newer docking program, AD Vina, is more accurate in "positive control" experiments. In addition, AD Vina typically runs 10 to 100 times faster than AutoDock. In some cases however, AutoDock can be more accurate than AD Vina - each provides complementary types of data that researchers may want to compare to each other. Therefore, as of July 2013, either one or both of these software programs are used on this project depending on the types of molecules being docked and the particular target against which they are docked. Both AutoDock and AD Vina are used in the FightAIDS@Home project on World Community Grid to dock millions of different small molecules to HIV protease, HIV integrase, and HIV reverse transcriptase, so the most promising molecules can be computationally identified, and then procured and tested in the laboratories of collaborating experimentalists to determine how potent they are at shutting down the activity of the enzymes that the HIV virus uses to replicate and spread. By joining together, The Scripps Research Institute, World Community Grid and its growing volunteer force can find better HIV treatments much faster than ever before.
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Re: WCG FightAIDS@Home Phase 1

Unread post by Alez » Fri May 12, 2017 2:27 pm

From WCG website

About the Project

FightAIDS@Home: A Layperson's Explanation

AIDS stands for "Acquired Immune Deficiency Syndrome." AIDS is caused by a virus called HIV — the Human Immunodeficiency Virus. When a human body is infected with HIV, it will work to fight the infection by making "antibodies," special molecules that are supposed to fight HIV.

Having HIV disease — or being HIV-positive — is not the same as having AIDS. Many people live with HIV, and do not get sick for many years. However, because the human body cannot generate antibodies that can eradicate HIV, as HIV disease continues, it slowly wears down the immune system, infecting key cells of the immune system and impairing their function or even destroying them. Eventually, HIV infection results in progressive depletion of the immune system, leading to "immune deficiency." The immune system is said to be "deficient" when it can no longer fulfill its role of fighting off infection and cancers. People with cellular immune deficiency are much more vulnerable to very rare infections such as tuberculosis, which can spread and mutate into drug resistant forms.

HIV remains a difficult target to stop because when it replicates, it does not do so perfectly and is thus continually changing. Scientists — like those at The Scripps Research Institute — have been studying HIV intensively to find ways to stop the onset of AIDS. The FightAIDS@Home Project is searching for drugs that can disable a key step in HIV's life cycle — specifically by blocking HIV-1 protease.

Blocking HIV Protease

Proteins are the basic building blocks in all of life's functions. (You can read more about them in the description of the Human Proteome Folding project.) Proteins are long chains of smaller molecules called amino acids. Enzymes are particular kinds of proteins that accelerate biochemical reactions. A protease ("pro-tee-ace") is an enzyme that is able to cut proteins apart at some point along the amino acid chain. For example, when you eat food containing protein, the protein molecules are cut apart into smaller amino acid molecules by proteases in your stomach. Your body can then use the amino acids to build the proteins it needs. While only a small percent of all of the proteins in an organism are proteases, they are very important in the proper functioning of its life processes.

But not all proteases are good. HIV makes and uses a particular protease, HIV-1 protease, which it uses to make the virus's different proteins.

This is where ligands play an important role. Ligands are small molecules that come from outside the cell that attach, or "bind," to pockets in proteins. These pockets are sometimes called receptors. You can think of a ligand binding to its receptor like a key fitting into a lock. The FightAIDS@Home Project is searching for ligands (drugs), which can attach to the HIV-1 protease receptor in a way that blocks its ability to function as an enzyme. This prevents the virus from spreading further in the body and developing into AIDS. Molecules that block HIV protease are called "protease inhibitors."

Your device will help by simulating the attachment process (docking) of many ligands to the HIV-1 protease, using one of two computer programs called AutoDock and Vina. The most promising ligands will be studied in more detail by scientists and should lead to better protease inhibitor drugs for controlling HIV and ultimately preventing the onset of AIDS.

For more about the agent running the FightAIDS@Home project, click here.
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Re: WCG FightAIDS@Home Phase 1

Unread post by Alez » Fri May 12, 2017 2:37 pm

From WCG website

A decade of progress is just the beginning in our fight against AIDS
By: Dr. Arthur Olson
Professor, The Scripps Research Institute
11 Nov 2015

Summary
In this extensive update, the FightAIDS@Home team leader, Prof. Art Olson, recaps nearly a decade of progress in the fight against AIDS: new computational methods, new understanding of key HIV proteins, and huge volumes of computational results that have only begun to be explored. Though Phase 1 is winding down, Phase 2 of this enormous project will continue to advance vital research into the world's deadliest virus.

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The FightAIDS@Home (FAAH) project joined World Community Grid almost 10 years ago, and is its longest continuously running project. Phase 1 is currently winding down, so it's a good moment to give World Community Grid volunteers a summary of who we are, what our goals have been, what computational approaches have been enabled by the resources you have provided, and what we've accomplished to this point. We're continually aware that this research is only possible because of your incredible generosity, and we hope you will all stay involved in Phase 2 of our work.

Who is behind FightAIDS@Home?

FAAH, which uses computational studies to help advance the search for new treatments against HIV/AIDS, began on Entropia (a now-defunct distributed computing platform) in 2000 as a collaboration between Scott Kurowski, Tim Cusac, Dr. Garrett Morris, and myself. On November 21, 2005, FAAH joined World Community Grid. During the last decade, the constantly increasing computing power provided by World Community Grid volunteers enabled us to expand the scale of our HIV research by many orders of magnitude. As an added bonus, these tremendous resources also inspired us to create new tools and strategies to harness the potential provided by World Community Grid. These tools are not only increasing the efficiency and accuracy of our own computationally-driven studies against HIV, but also help advance the research that the rest of the scientific community pursues against other diseases.

The FightAIDS@Home project has been run in the Olson Laboratory by a dedicated succession of Postdoctoral Research Associates over the past 10 years. Garrett Morris, William "Lindy" Lindstrom, Alex Perryman, and Daniel Santiago have in turn taken the lead in running our computational experiments on World Community Grid. They have been assisted over the years by several lab members including Michael Pique, Ruth Huey, Stefano Forli, Sargis Dallakyan, Alex Gillet, and Max Chang. As in most academic labs, postdocs stay for a period of 2 to 4 years and then move on to more permanent positions. Daniel Santiago has just left the lab, and we are currently interviewing for a new Postdoctoral Fellow to take his place.

FightAIDS@Home goals

The Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immunodeficiency Syndrome (AIDS), has infected over 70 million people throughout the world since this pandemic began. Currently, over 35 million people are infected with HIV, and there are over 2 million new infections each year. Almost one million people die from AIDS each year, which makes HIV the deadliest virus that afflicts humanity.

The Olson Lab is interested in understanding the molecular mechanisms responsible for the evolution of drug resistance in HIV, and in using that understanding to help develop new therapeutic approaches to treat HIV-infected individuals. I direct an NIH-funded center called the HIVE (HIV Interaction and Viral Evolution) Center, which is composed of 14 individual laboratories in 8 different institutions around the country. The Olson laboratory, as well as that of Prof. Ron Levy at Temple University, is involved in the computational aspects of the goals of the Center. Our approach to the problem of drug resistance has been to simulate the interactions of synthetic organic molecules with viral proteins to predict which ones might bind to and affect the activity of these proteins. To do this, my Lab has developed and use two computational docking programs AutoDock and AutoDock Vina to screen large libraries of chemical compounds. The primary goal in these computations is to discover which compounds can potentially interact with and inhibit the activities of the so called "wild type" and drug resistant mutations of the proteins that have evolved in treated patients. The primary protein targets for this work have been the HIV protease (PR), integrase (IN), and reverse transcriptase (RT). These are the three proteins for which the FDA has approved drugs for the treatment of HIV-infected patients. They are also the three enzymes that the virus produces to carry out the chemical reactions that sustain the viral life cycle. By using the extensive structural data on wild type and mutant proteins, as well as mutational data from treated HIV-infected patients, we explore hypotheses and relationships between molecular structure and the development of drug resistance. The computational resources of World Community Grid have been invaluable in extending our computational approaches in this research effort.

In the initial years of FAAH, experiments generally involved computationally evaluating a few thousand compounds against one pocket of one type of the viral machinery - the active site of HIV protease. The "active site" is the region where the chemical work gets accomplished by an enzyme. HIV protease chops the long, viral, multi-protein polypeptide chain at several different, specific places. By cutting that multi-protein chain into different pieces, it then allows those different, individual proteins to fold up into their normal, mature shapes that are required for them to function. Those folded viral proteins work together to create new HIV particles that escape the infected cell, mature, and then infect new cells, which spreads the infection within the patient and allows the infection to spread to new people. When HIV protease activity is sufficiently disrupted, then those multi-protein viral polypeptide chains are no longer separated in an efficient, well-ordered manner. This causes the infected cell to produce immature, non-functional particles that are not able to infect other cells. Of greatest importance, when HIV protease drugs were combined with HIV reverse transcriptase drugs, the death rate associated with HIV infections drastically decreased. Before HIV protease drugs existed, getting HIV was basically a rapid and horrible death sentence. When HIV protease drugs were combined with other classes of anti-HIV drugs to make the HAART cocktails (Highly-Active Anti-Retroviral Therapy), then many HIV patients were able to live long, productive lives with a reasonable quality of life. However, since HIV keeps evolving into slightly different forms that are able to resist the effects of these drugs (that is, new multi-drug-resistant mutant superbugs keep appearing and spreading), we need to discover new types of drugs and therapeutic interventions that can disable these mutants.

World Community Grid enables unprecedented computational approaches for FAAH

The computational docking problem is a high-dimensional search of possible interactions between two molecules, a chemical compound and a target viral protein. One must typically generate millions of poses of the two interacting molecules, and for each pose compute the energy of interaction between them. This energy evaluation is accomplished by summing up the interaction energies between all of the atoms in the two molecules. When we first developed AutoDock in 1990, a single docking would take 20 minutes or more on the fastest computers of that time. Today, thanks to Moore’s Law, such a calculation may take a few seconds to a minute depending on the complexity of the molecules involved. Thus, the ability to screen many molecules against a specific protein target (i.e. virtual screening) became possible. However, finding a good candidate molecule (a hit) that binds well to a functional site on a protein requires screening a very large number of chemical compounds. The larger the library of compounds, the better the chances that a good hit compound will be in that library.

Having our FAAH project on World Community Grid has enabled us to run computations that would have taken literally hundreds of years on more conventional computer systems. We are now able to run virtual screens of chemical libraries against not a single protein target, but large panels of drug resistant mutant proteins of that viral target. The computing power of World Community Grid has also enabled us to increase the size of the libraries that we use in our virtual screens. Previously we were only able to screen libraries of a few thousand compounds. Today we typically screen combined libraries containing over 5 million compounds against each HIV protein target. This gives us a much better chance of finding good hit molecules.

A critical aspect of computational docking is how the interacting molecules are represented or modeled. AutoDock was the first docking code that allowed the model of the chemical compound to be flexible when docking to a protein target. Each rotatable bond in the compound added another dimension to the search space that had to be explored, and thus to the complexity of the computation. In those days, the target protein had to be treated as a rigid molecule, since the complexity of its flexibility would be too computationally difficult to simulate. Using the power of World Community Grid, we have been able to overcome this restriction, and have implemented different representations of protein flexibility, giving us more realistic models of the protein target. To this point FAAH volunteers have donated over 340,000 years of computing time to our research efforts.

Scientific accomplishments

By screening libraries of compounds against both wild type and numerous drug resistant mutant versions of HIV protease we have been able to characterize the range of the mutants that exist and cluster them into characteristic variants. This has given us a way to reduce the number of prototypic mutants of HIV PR that we need to use in our virtual screens, and has enabled us and others to focus our attention on the kinds of variations that the virus is capable of making to remain functional in the presence of drug therapies.

As the number of World Community Grid volunteers and the amount of computer power they donated increased through the years, we have been able to greatly increase the size and complexity of the types of experiments we could perform. We have now docked millions of small molecule compounds against several different regions of all of the enzymes that HIV produces—protease, reverse transcriptase, and integrase. HIV reverse transcriptase is the part of the viral machinery that makes new copies of its genetic material. It takes the HIV RNA from the original viral particle and makes a more stable DNA version of it (called cDNA, or complementary DNA). HIV integrase then processes the viral DNA, by clipping part of each end off of it, to generate more reactive “sticky ends.” Integrase then permanently attaches the sticky ends of the viral DNA into our human DNA, to create a permanently infected cell, which will then go on to produce new copies of the virus. Thus, World Community Grid enabled us to computationally evaluate millions of compounds against many different regions of all of the viral machinery—instead of only being able to evaluate thousands of compounds against one region of one type of enzyme. It will take us many years to analyze these mountains of data, select the most promising candidate compounds, and experimentally evaluate these candidates in “wet lab” experiments performed by our collaborators. But we have created new tools to help us process and analyze these data more efficiently, and we are developing additional approaches to help us harvest more useful and more accurate information from the results that volunteers like you have produced.

Most recently, we have turned our attention to the concept of synergistic inhibition of HIV enzyme function. In addition to targeting the active sites of these enzymes, we have also been able to search for new inhibitors that bind to “allosteric” sites on each of these viral nanomachines. Allosteric inhibitors have been discovered in both HIV integrase and reverse transcriptase. Most inhibitors disable the function of an enzyme by binding directly to the “active site” (the specific region of an enzyme where the chemical work occurs) and blocking its ability to function. The 9 FDA-approved HIV protease drugs are an example of these conventional types of inhibitors: they bind to and block the active site in the hollow tunnel in the center of protease, which prevents the viral multi-protein polypeptide from being able to bind within that tunnel and get cleaved. Allosteric inhibitors work in a very different way—they bind to a totally different site, regulate the conformational preferences and/or flexibility of the entire target protein, and thereby disable the active site. They bind far from the active site and project their influence over the rest of the enzyme. Allosteric inhibition is like putting a latch on the handles of a pair of scissors in order to prevent the blades from being able to open and close and cut things. Most importantly, different experiments with HIV, cancer, and malaria have shown that combinations of allosteric inhibitors and active site inhibitors can (a) generate combination therapies that are more effective against current superbugs and that (b) actually slow down the evolution of new drug-resistant mutants.

There are no known allosteric inhibitors of HIV PR. However we have postulated that there may exist sites for allosteric inhibition of HIV PR. We have run FAAH virtual screens against candidate sites, and have found that there are chemical compounds that can bind to these sites. These observations are bolstered by experimental x-ray diffraction experiments on PR in the presence of a chemical fragment library. Observed in these experiments are 3 sites that are distal to the active site of HIV PR where chemical fragments bind. We have now focused on finding better binding compounds at these sites using our FAAH virtual screens. Some of the hits from of these screens have been verified by x-ray crystallography and NMR spectroscopy. Further development and optimization of these hits is ongoing. We are also working closely with other HIVE Center investigators, Prof. Kvaskhelia at Ohio State University, and Prof. Arnold at Rutgers University on improving allosteric inhibition for HIV integrase and reverse transcriptase, respectively.

As stated above, we have only scratched the surface in terms of analyzing the enormous data sets that have been produced on World Community Grid. Typically we have only selected and looked at the very top candidates from a large virtual screen. Since the energy evaluation from docking is only a crude approximation of the true energy of binding, we, in fact could be selecting compounds that are not the best binders – so-called "false positives." If we suggest to our collaborators to synthesize or buy such compounds, it can be very costly in time and money. Thus we are starting several efforts to reduce the number of false positives that arise from our virtual screens. Some of these efforts involve data mining of all of the FAAH results, looking at the interaction patterns of all of the compounds that are docked. This data can give us some chemical signatures that allow us to filter out the false positives from the true binders. This is ongoing work, but initial results look very promising.

Refining results

Another approach to this problem that has been developed in collaboration with the Levy Lab at Temple University involves a separate computational step that evaluates not just the top-scoring compound from a virtual screen, but many of the top ranked compounds. This computation uses sophisticated molecular dynamics based estimates of the free energy of binding, which are too computationally difficult to perform during the docking, but which can discriminate between true and false positives subsequent to the docking. This approach, called BEDAM, is being implemented with a molecular simulation tool called Academic IMPACT which is running on Phase 2 of our FAAH project on World Community Grid.

In summary, World Community Grid volunteers have enabled an invaluable resource for our ongoing work in understanding the nature of drug resistance in HIV. As with most scientific projects, along with new results, new questions arise. Although we have yet to get a complete picture of the evolution of HIV drug resistance or create a new drug that defeats HIV resistance, we have developed new computational methodologies and have opened a number of avenues of research, that may lead to better approaches to treating and possibly even curing HIV infection.

A sincere thank you to all of the volunteers who donated their time to this project. And while the initial phase of the FightAIDS@Home project has come to an end, be sure to contribute to the second phase of the project.
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Re: WCG FightAIDS@Home Phase 1

Unread post by Alez » Fri May 12, 2017 3:12 pm

From WCG website

FightAIDS@Home Team Re-Opens Phase 1
By: The FightAIDS@Home research team
1 Dec 2016

Summary
We are happy to announce that we are re-opening Phase 1 of the Fight AIDS@Home project. In collaboration with World Community Grid, and thanks to their affiliated volunteers around the globe, High Throughput Virtual Screening will be performed by targeting the HIV-1 capsid protein with the goal of discovering new chemical compounds to defeat the AIDS virus (HIV). Read more in this update.

Background

During the maturation of the HIV virus, the HIV-1 capsid protein (CA) assembles with thousands of copies to forms the capsid core [ref 1] with a characteristic conical shape (see Figure 1C). This core encloses the RNA viral genome. Upon the entry of the HIV in host cells, the capsid core is released into the cytoplasm, and it dissociates in connection with the reverse transcription in a not completely understood process. This leads to the importation of DNA viral genome in the host cell’s nucleus, where it is integrated in the host DNA to finalize the infection.

The critical role of CA protein, in early and late stages of the viral replication life cycle, has led to recent efforts on drug development, targeting the mature form of the protein. Currently, none of these molecules are used in clinic, and some face natural polymorphism and resistant mutations [ref 2]. Therefore, continued development of drugs targeting the CA protein is still needed

Different level of the capsid protein structure

CA protein consist of a sequence of 231 amino acids which folds into 3 different domains (Figure 1A): The N-terminal domain (N-ter), the linker, and the C-terminal domain (C-ter). This protein chain complexes with other chains to form hexamers (Figure 1B) or pentamers; which assemble together to form the fullerene-cone shape of the capsid core (Figure 1C). There are several models of the core assembly, but all are composed of ~200 hexamers, and exactly 12 pentamers.

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Figure 1: The HIV-1 capsid protein structure

High Throughput Virtual Screening

The FightAIDS@Home team is working with World Community Grid to find active compounds which could attach to the CA proteins and mediate the assembly of the capsid core. This computational experiment will be performed using the docking software AutoDock VINA [ref 3].

Thanks to the volunteers, around 2 million molecules will be screened across ~50 conformations of the capsid protein, and hopefully lead to a reduced selection of molecules. This will be the starting point of a drug discovery process targeting the HIV-1 capsid protein.

With the support of our collaborators from the HIV Interaction and Viral Evolution (HIVE), experimental biding assays and infectivity assays will be conducted to determine if the selected compounds could be optimized as a promising drug candidate.

Four pockets of interest

Based on X-ray structures of CA protein, models of the core, and computational analysis of their flexibility, four pockets of interest have been selected on the surface of the hexamer assembly (see Figure 2).

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Figure 2: Four pockets of interest

These pockets involve either one monomer (as pocket 2 along the linker domain), at the interface of two monomers (pocket 1 & 4), or at the six-fold interface (pocket 3).

Mutagenesis experiments revealed that core stability is fine-tuned to allow ordered disassembly during early stage of virus replication cycle [ref 4]. This is why selection of compounds will be done either for molecules which could stabilize or destabilize the hexamer; assuming that both actions could have impacts on the equilibrium of the core.

Our team from The Scripps Research Institute of San Diego, which includes Dr. Pierrick Craveur, Dr. Stefano Forli, and Prof. Arthur Olson, really appreciates the support this project receives from World Community Grid volunteers around the globe.

References

Briggs, J. A. and H. G. Krausslich (2011). "The molecular architecture of HIV." J Mol Biol 410(4): 491-500.
Thenin-Houssier, S. and S. T. Valente (2016). "HIV-1 Capsid Inhibitors as Antiretroviral Agents." Curr HIV Res 14(3): 270-282.
Trott, O. and A. J. Olson (2010). "AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading." J Comput Chem 31(2): 455-461.

Forshey, B. M., U. von Schwedler, et al. (2002). "Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication." J Viro
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Re: WCG FightAIDS@Home Phase 1

Unread post by scole250 » Fri May 19, 2017 10:48 pm

I'm running this under linux and it's paying extremely well.
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Re: WCG FightAIDS@Home Phase 1

Unread post by Alez » Mon Jun 19, 2017 1:48 pm

FightAIDS@Home Targeting a Key HIV Protein
By: The FightAIDS@Home research team
15 Jun 2017

Summary
FightAIDS@Home researchers restarted the first phase of the project at the end of 2016, and in just a few months, they have completed approximately 46 percent of their projected work on World Community Grid. Read about their progress on finding compounds that could stop HIV from replicating.

Background

FightAIDS@Home is searching for possible compounds to target the protein shell of HIV (called a capsid), which protects the virus. Currently, there are no approved drugs that target this protein shell.

The virtual docking techniques used in Phase 1 are an approximation of the potential effectiveness of promising compounds. Phase 2 of FightAIDS@Home uses a different simulation method to double-check and further refine the virtual screening results that are generated in Phase 1.

The research team is examining a library of approximately 1.6 million commercially available compounds to find promising treatment prospects. The team estimates that they will need to carry out roughly 621 million docking computations on World Community Grid to thoroughly test each potential compound. With the help of many volunteers who are supporting this project, they’ve already completed 46 percent of their goal.

You can keep up with the research team’s progress on their website, which includes frequent updates on their experiments and progress.

Please read below for a detailed look at the technical aspects of their recent work.

Insilico search for novel drugs targeting the HIV-1 mature capsid protein

The importance of the capsid protein

The capsid protein (CA) plays crucial roles in the HIV replication cycle1. After viral and host cell membrane fusion, the capsid core is released into the cytoplasm. This core, which corresponds to the assembly of ~1200 capsid proteins, contains and protects viral RNA and proteins from degradation. Reverse transcription occurs in the core in a process which is tightly connected to the capsid core disassembly. This leads to the import of the cDNA viral genome into the host cell’s nucleus, where it is integrated into the host DNA to finalize the infection.

To date, no drugs targeting CA are approved for clinical use. With the goal of identifying novel active molecules which destabilize the capsid core, we set up a high throughput virtual screening (VS) campaign in collaboration with World Community Grid as part of the FightAIDS@Home (FA@H) project.


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Figure 1: PDB 4xfx, the hexamer structure of the native HIV-1 mature capsid protein. (Credit: Pierrick Craveur)

Targeted structures

The main target of the docking calculations was the recently solved structure of the CA hexameric assembly2. Four pockets of interest were selected at the surface of the hexamer in order to perform focused dockings, mainly at the CA-CA dimer interfaces. Structural variability surrounding these pockets was analyzed by comparing this X-ray structure from the PDB (4xfx, see Figure 1), and the two full capsid core models assembled by Schulten's lab3 (3j3q and 3j3y, see Figure 2). Based on that, 36 different conformations were selected as targets for the VS, including the X-ray structure and structures from the models. Each target was set as full rigid and also with a specific combination of residue side chains defined as flexible.

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Figure 2: The 2 models of the capsid core assembly. (Credit: Pierrick Craveur)

An extended library of ~1.6 million commercially available compounds was used for the screening. Replicate computations were performed for each docking experiment in order to assess the consistency of the results. In total ~621 million docking computations will be performed on World Community Grid. For the time being, ~46% of the computation is completed, with an ending date estimated at the end of 2017 if the computation does not increase in speed. However, in one month we will be able to propose to our collaborators from the HIVE Center a selection of compounds (focusing one of the four pockets) for experimental binding and infectivity assays.

Other information

Dedicated web pages (see fightaidsathome.scripps.edu/Capsid/index) were developed to inform the public and the World Community Grid volunteers as the project advances. The pages contain an overview of the project, details on targets and the selection process, a description of the compound library, an hourly updated status of the computations, and a “people” section where volunteers can appear in the page to be fully part of the project.

An automatic pipeline has been developed in order to constantly post-process the docking results received from World Community Grid. These post computations involve the High Performance Computing (HPC) cluster from The Scripps Research Institute, and are mainly related to the identification of the interactions between drug candidates and the CA protein. The pipeline ends in filling a MySQL database, which will be made public as soon as it will be stable. In details, 3.3TB of compressed data are estimated to be received from World Community Grid, and 1TB to be generated after post-processing.

Our team from The Scripps Research Institute of San Diego, which includes Dr. Pierrick Craveur, Dr. Stefano Forli, and Prof. Arthur Olson, really appreciates the essential support this project receives from World Community Grid volunteers around the globe.

References

1. Campbell, E. M. & Hope, T. J. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol 13, 471-483, doi:10.1038/nrmicro3503 (2015).

2. PDB 4xfx : Gres AT, Kirby KA, KewalRamani VN, Tanner JJ, Pornillos O, Sarafianos SG. X-Ray Structures of Native HIV-1 Capsid Protein Reveal Conformational Variability. Science (New York, NY). 2015;349(6243):99-103.

3. PDB 3j3q & 3j3y : Zhao G, Perilla JR, Yufenyuy EL, et al. Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature. 2013;497(7451):643-646.
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