Two Compounds Discovered that Pave the Way for New Class of AIDS Drug

IBM World Community Grid’s Computing Strength Powers Breakthrough Research that will Guide their Development

02 Mar 2010: A team of researchers at the renowned Scripps Research Institute has discovered two new compounds that prove the existence of new binding sites on HIV protease.  Associate Professor C. David Stout, senior author of the study, explained “These results open the door to a whole new approach to drug design against HIV protease,” which is an enzyme used by HIV to create new, infectious viral particles.

For video and to Read more.

Summary
World Community Grid is pleased to launch the Discover Dengue Drugs - Together - Phase 2 project by The University of Texas Medical Branch (UTMB) in Galveston, Texas, USA and the University of Chicago in Illinois, USA. The mission of Discovering Dengue Drugs – Together - Phase 2 is to identify promising drug leads to combat dengue, hepatitis C, West Nile, Yellow fever, and related viruses.

Read more.

GPUGRID will be the essential computational tool in a national publicly funded project (TV3-Marato) on Schizophrenia. The aims of the project is to perform in-silico modelling of antipsychotic drug actions. One of the previous task group called *JAN* were already starting to study this problem. Thanks in advance to all volunteers and stay tuned for updates. GDF 5 Mar 2010 14:35:42 UTC

March 16, 2010: We are preparing the screening experiment by neuroblastoma cells to evaluate 10 candidates as a drug for neuroblastoma.

GPUGRID paper published!
We are happy to announce that the Journal of Chemical Information and Modeling has published the paper about GPUGRID. In this publication we formally introduce GPUGRID to the scientific community (technically and in terms of applications) and we show some results of the *IBUCH*pYEEI* workunits. You can read the abstract here http://tinyurl.com/gpugridpaper Thank you very much. GPUGRID team 14 Mar 2010 9:10:11 UTC

Five Years, Half a million members,
and 300,000 Years of Service to Society

TACC, IBM and World Community Grid celebrate research milestones

08 Mar 2010 

Texas Advanced Computing Center, IBM and World Community Grid celebrate research milestones

Category: All
Tags: Video and Media

Summary
Texas Advanced Computing Center (TACC) and World Community Grid have played a key role in helping Dr. Stan Watowich, from The University of Texas Medical Branch, complete Phase 1 of his research project to discover chemical compounds that can be effective against Dengue Fever.

World Community Grid members have contributed more than 320,000 years of volunteer computing time to solve pressing scientific problems. The Texas Advanced Computing Center (TACC) has supported World Community Grid both as a resource provider and as an active collaborator on several of the research projects. TACC and World Community Grid helped Dr. Stan Watowich, the Principal Investigator for the "Discovering Dengue Drugs – Together" project, complete Phase 1 of his research project. Phase 2 is now underway.

HPF2 Update - March 2010

Greetings WCG Volunteers,

We've been working diligently to develop a pipeline for a cooperative analysis of phylogenetic and structural data. We will integrate our structure predictions with knowledge of how proteins (and functional sites on folded proteins) evolve, by estimating the phylogenies of all protein domain families in our database and identifying positively-selected amino acid sites in these families using codon-based molecular evolution models that can be mapped onto the predicted structures. The first stages of this analysis are coming to fruition, and we've begun investigating preliminary results.

Using phylogenetic models, we intend to identify sites of proteins exhibiting evolutionary pressure. This may improve our understanding of how proteins evolve new functions and structures, and will ultimately lead to an increase in genome annotation for proteins whose purpose we know next to nothing about. The great scale of and wealth of information in our database may allow us to improve upon our existing and future de novo structure and function predictions. Identifying structurally or functionally importing residues in protein domains should inform our comparative modeling techniques. We use probabilistic methods to produce models of evolution using observed rates of mutation in protein families. Lots of different evolutionary pressures affect the mutation and expression of proteins, but we hope to garner insight with this analysis about how evolution adapts protein function.

Using our automated methods, we produced evolutionary models for a handful of identified protein domain families in major plant genomes. One such protein family matches PDB 1TQE "Myocyte Enhancer Factor-2". While this analysis is very preliminary (and I stress preliminary), positive selection analysis identifies a few residues that may be involved in DNA binding and the integrity of the dimer near the substrate. This is the kind of science we'll be investigating in the future using WCG predicted structures.
--
Patrick Winters
Bonneau Lab

 Graphics, charts and more.

Experiment 32: 0% Completed

Experiment 32 involves screening the Otava library of approximately 335,000 "building blocks" (i.e., fragments) against the active site of 7 different versions of HIV protease. All but one of these target conformations were generated by Dr. Alex L. Perryman's Molecular Dynamics (MD) simulations of 5 different variants of HIV protease. These 7 targets include 2 snapshots of the V82F/I84V mutant from ALP's 2004 paper in Protein Science. These 2 snapshots of a multi-drug-resistant "superbug" have semi-open conformations of the flaps, which makes these models good targets for the "eye site" that is located between the tip of a semi-open flap and the top of the wall of the active site. The 3rd target is the equilibration MD (EqMD) output for 1HSI.pdb, which is a semi-open conformation of HIV-2 protease. HIV-2 is the group of strains of HIV that are most common in Africa. We'll be targeting the "eye site" of 1HSI, as well. The 4th target is the EqMD output from 1MSN.pdb, which was created using a different crystal structure of the V82F/I84V superbug. This model has a closed conformation of the flaps, which means that we'll be targeting the floor of the active site. The 5th target also has a closed conformation of the flaps, but this EqMD output is from 2R5P.pdb, which is the wild type HIV-1c protease. HIV-1c is the group of strains of HIV that are most commonly found in Asia. The 6th target has semi-open flaps, and it is the EqMD output from 1TW7.pdb, which is a superbug with the mutations L10I/D25N/M36V/M46L/I54V/I62V/L63P/A71V/V82A/I84V/L90M. We'll be targeting the eye site of this superbug, too.

The 7th target is a crystal structure of the wild type HIV protease with 5-nitroindole bound in the eye site. This new crystal structure from Prof. C. David Stout's lab was presented in the Supporting Information for our recent article in Chemical Biology and Drug Design, vol. 75: 257-268 (March 2010). This new research article of ours was recently discussed in a press release on Science Daily and in a news story on KPBS-FM. I deleted the 5-nitroindole fragment from this structure before generating the AutoDock input file for this target. We'll be screening new fragments against this crystal structure's eye site, as well.

The Protein Data Bank is located at http://www.rcsb.org/pdb/home/home.do. You can search the PDB using the 4 character codes listed above (i.e., before the .pdb suffix) to learn more about each of these targets.

This experiment involves faah11647 - faah13,984.

These calculations have not yet started.

Member News

World Community Grid is pleased to announce that as a result of the generous contribution of computing power from our members, the Nutritious Rice for the World project finished on April 6, 2010.

The project was launched on May 12, 2008. While it was active, World Community Grid members processed over 29 million results which required nearly 26,000 years of computing power. This work would have taken about 200 years of time using the computing resources available to the researchers at the University of Washington. Using World Community Grid, this research was completed in less than two years.

With this project's completion, our members have significantly contributed to the research that is being done to ultimately develop rice strains that will make a difference in fighting malnutrition and feeding the world’s people.

Now comes the difficult part of sifting through the data to find the best models. The researchers need to find the best models from the almost 7 billion models generated. This should take approximately 3-6 months using their fastest methods. After identifying the most accurate models, they will use the information to figure out what functions these proteins perform in the rice organism. This involves comparing the structure and sequence to known proteins which is also a time consuming process. The plant genomes are not nearly as well studied as the human and mammalian genomes which makes the process all the more difficult.

You may read about these plans and get the latest update from The Nutritious Rice for the world scientists in this forum thread or on their website.

The Nutritious Rice for the World research staff at the University of Washington, USA wish to express their sincere gratitude to you for contributing your computer power to this project. 

New publication - RBoinc: scientists interface to DC
A new publication with the title "Distributed computing as a virtual supercomputer: tools to run and manage large-scale BOINC simulations" by GPUGRID scientists and developers Toni Giorgino, Matt Harvey and Gianni De Fabritiis, has been accepted for publication in the journal of Computer Physics Communications (DOI: 10.1016/j.cpc.2010.04.007) pdf. Scientists at GPUGRID have been using RBoinc already for a year and has proved to be a very safe and useful tool to manage work-flows in high-throughput experiments. RBoinc is already in the official BOINC source repository. 22 Apr 2010 12:49:53 UTC

Summary
The Help Conquer Cancer project researchers have developed an image-analysis and classification system for automatically scoring images from high-throughput protein crystallization trials.

Non-technical abstract:

The structure of cancer related proteins is important to know because their shape determines their function and role in the disease process. These proteins are usually large, so the only way to determine their structure is using x-ray crystallography. What makes this exceedingly time consuming is the necessary first step of getting the protein to crystallize. To do this, the scientists mix in varieties of compounds in the hope that this will help spur the crystallization of the protein. Using robots, many thousands of crystallization attempts are made. To determine if a crystal actually formed requires human observation and this is very time consuming.

By using World Community Grid, the scientists were able to developed an automated system for analyzing the images of the crystallization attempts and recognizing whether crystallization occurred. They have already trained the system to successfully recognize 80% of crystal-bearing images and eliminate 98% of clear drops. This significantly reduces the time required for human inspection, which should lead to much faster structure determination of proteins under study.

Eventually this should lead to a better understanding of the role of certain proteins in cancers and other diseases, which in turn should lead to identifying better treatments for these diseases.

Technical Abstract:

We have developed an image-analysis and classification system for automatically scoring images from high-throughput protein crystallization trials. Image analysis for this system is performed by the Help Conquer Cancer (HCC) project on the World Community Grid. HCC calculates 12,375 distinct image features on microbatch-under-oil images from the Hauptman-Woodward Medical Research Institute’s High-Throughput Screening Laboratory. Using HCC-computed image features and a massive training set of 165,351 hand-scored images, we have trained multiple Random Forest classifiers that accurately recognize multiple crystallization outcomes, including crystals, clear drops, precipitate, and others. The system successfully recognizes 80% of crystal-bearing images, 89% of precipitate images, and 98% of clear drops.

Journal that the paper appeared in: Journal of Structural and Functional Genomics.

For access to the paper, please click here.
WCG news article

The Nutritious Rice for the World(Rice) project, a World Community Grid BOINC project, ended a few weeks ago. BOINC (Berkeley Open Infrastructure for Network Computing) is a non-commercial program and infrastructure which allows volunteers to donate their computer’s spare computing resources to take part in very interesting, computing intense scientific projects. Many people around the world contributed their CPU-resources to help figure out the structure of proteins of the most common strains of rice. In the end, about 25,761 years of CPU-time were contributed to the project. IBM heavily contributed to this project through their World Community Grid (WCG) program, offering Rice a massive userbase and community.

Read More

28 Jun 2010 

Launch of The Clean Energy Project - Phase 2

Tags: Project Update 

Summary
World Community Grid is pleased to launch the Linux version of The Clean Energy Project - Phase 2 (CEP2). This project is provided by the Department of Chemistry and Chemical Biology, Harvard University in Cambridge, Massachusetts, USA and hopes to find promising new materials for organic solar cells. 

15 Jun 2010 

Surplus PC Power Yields Faster Cancer Research

Category: Help Conquer Cancer
Tags: Publications and Presentations 

Summary
World Community Grid project automates tedious process to determine if protein samples are ready for x-ray examination.

Using World Community Grid, the Help Conquer Cancer project scientists have devised a way to automate and accelerate a manual, complex process that enables researchers to more easily discover the structure of cancer-related proteins, and, eventually, formulate cancer cures. This new, automated approach may also help the exploration of other diseases and food-related research. 

To read more about this exciting announcement, please click here. 

The following video accompanies the press release. We hope that you enjoy watching it. 

Video

01 Jun 2010 

Fiocruz researchers publish paper for Genome Comparison project

Category: Genome Comparison
Tags: Publications and Presentations 

Summary
The researchers from Fiocruz have published a paper for their database about the results of the Genome Comparison project. This project included the comparative analysis of the genomes of more than 300 organisms. This database is now available for use by researchers throughout the world. 

With Folding@home (FAH), we have the computer power to tackle challenging problems involved with protein folding.  One of the interesting folding-related problems has to do with how proteins (and their conformational change) catalyze viral infection.  While viral infection is not a major thrust of FAH, it has been a pilot project for several years.  

We are happy to announce the publication of some of our recent FAH scientific results:
"Atomic-Resolution Simulations Predict a Transition State for Vesicle Fusion Defined by Contact of a Few Lipid Tails"
This work represents a major step forward in this project, as we can now study the process in all-atom detail and get some better sense of the role of proteins and protein conformational change in the process.

 READ MORE

12 Jul 2010 12:49:18 UTC 

Dear crunchers,

In the past months you crunched a set of WUs that aimed at observing a free ligand binding to a protein (*IBUCH_esrever*). At least 1 of the 750 simulations has reached destination!  Congratulations for this amazing result. However, we lack a bit of statistics for this event and we need to get more of these. We are extending the experiment (*IBUCH_freebind*). They're sitting in the queue, get yours! 

Video

July 30, 2010

The FightAIDS@Home Project uses the volunteered computer power of IBM!s World
Community Grid to test candidate compounds against the variations (or “mutants”) of HIV that
can arise and cause drug resistance. FightAIDS@Home has identified several fragments as
new candidates for a novel binding site on the peripheral surface of HIV protease. These
potential allosteric fragments are being tested by our collaborators at TSRI. FightAIDS@Home
also recently (a) discovered many compounds that might be novel types of active site inhibitors
of HIV protease, (b) identified several candidates that docked well to the active site of our new
models of HIV integrase, and (c) discovered a potential allosteric inhibitor of a drug-resistant
mutant of HIV integrase. These compounds will be purchased and then tested by our
collaborators at The Scripps Research Institute.

FightAIDES@HomeNews Volume 9: July30 2010

 New Class of AIDS Drug? Two Compounds Lay Foundation, Help Combat Drug-Resistant Virus Strains - Science Daily

Updates for Project:

July 31, 2010

Hi to all! Thought to try to explain what we are doing right now before you take some vacation, like the scientists here. Hope it will help to feel that things are improving and that the project is very active from this side!! Actually, someone new will join the group on september, Anne Lopes. Anne is assistant professor in structural bioinformatics and has a background in physical-chemistry. She is very interested in working on the protein partnership problem with the numerical approach we developed and on the data analysis of the huge amount of information you are producing!

Read More on project complete with graphics and charts.

Project Status and Findings:  
Information about this project is provided on the web pages below and by the project scientists on the Drug Search for Leishmaniasis website. If you have comments or questions about this project, please visit the Drug Search for Leishmaniasis forum.

Mission
The mission of Drug Search for Leishmaniasis is to identify potential molecule candidates that could possibly be developed into treatments for Leishmaniasis. The extensive computing power of World Community Grid will be used to perform computer simulations of the interactions between millions of chemical compounds and certain target proteins. This will help find the most promising compounds that may lead to effective treatments for the disease. 

Significance
Leishmaniasis is one of the most neglected tropical diseases in the world. Each year this disease infects more than two million people in 97 countries. To date, there are no available vaccines to prevent the disease, in spite of multiple research efforts. Leishmaniasis is caused by a protozoan parasite (genus Leishmania) transmitted between human and animal hosts by female sand flies. One form of the disease, the "visceral" form caused by Leishmania infantum in America, mainly affects children, who can die if adequate treatment is not provided promptly. Existing control measures rely upon drug therapy, insect control and education in the affected communities. However, the number of human cases continues to increase in tropical countries such as Bangladesh, India, Sudan, Ethiopia, Brazil, Colombia, Peru and many others.

The classical treatments for all forms of Leishmaniasis can cause severe side effects, including death. Furthermore, drug resistant parasites are causing major problems in many endemic countries. For these reasons, there is an urgent need for new, safe and inexpensive anti-Leishmania drug compounds.

Approach
A software program called VINA from The Scripps Research Institute in La Jolla, California, will be used to perform the virtual chemistry experiments. These virtual experiments will search to find which of millions of drug compounds might be able to disable particular proteins, essential for the parasite's survival. Screening for the best potential drug compounds is an early step in the process of developing effective treatments for the disease. With enough computing power, this screening can be done much more quickly than using conventional laboratory experiments. However, existing computer facilities available to the researchers would require approximately 120 years to perform the screening. The power of World Community Grid can reduce the time required to less than one year. Information about the best candidate compounds will be published by the scientists, and this information will be available in the public domain for other scientists to build upon with their research. Further laboratory work using the best candidates identified by this project could lead to the development of better drugs to fight Leishmaniasis.