FightAIDS@home, поиск лекарств от ВИЧ и СПИДа Налаштування

[Rilian]

Проект занимается подбором лекарств от ВИЧ

* Официальный сайт
* Прогресс и статус исследований на официальном сайте

Как присоединиться читайте в главном топике World Community Grid

Подробнее о научных методах в FightAIDS@Home:

Белки, как вы уже знаете, является строительным материалом для всех живых существ. Разнообразные формы белков принимают участие во всех процессах, происходящих в живых организмах. Белки являются длинными цепями меньших молекул - аминокислот.

Энзимы являются конкретными типами белков, которые ускоряют биохимические реакции.

Протеаза - энзим, который способен «вырезать» отдельный белок в некоторой точке аминокислотной цепи. Например, когда Вы едите пищу, которая также содержит белок, белковые молекулы режутся на меньшие аминокислотные молекулы протеазой в вашем желудке.

Ваш организм может затем использовать получившиеся аминокислоты, чтобы формировать белки, которые ему нужны для продолжения жизнедеятельности. Стоит отметить также, что только небольшой процент из всех белков в организме является протеазами, поэтому эти белки очень важны в своем функционировании для обеспечения жизненных процессов.

Ваш компьютер поможет нам имитировать процесс присоединения множества различных лиганд* к HIV-протеазе (HIV- Human Immunodeficiency Virus – вирус иммунодефицита человека), для этого используется компьютерная программы под названием AutoDock.

*Лиганды - (от лат . ligo - связываю), в комплексных соединениях молекулы или ионы, связанные с центральным атомом (комплексообразователем), напр. в соединении [Co(NH3)6]Cl3 центральный атом - Со, а лиганды - молекулы NH3.

Перспективные лиганды будут изучены более подробно учеными, и это должно привести нас к созданию лекарства для управления ВИЧ-инфекцией, и в конце концов, к предотвращению заболевания СПИДОМ.

Естественно, моделирование таких процессов – сложная в вычислительном отношении задача из-за большого разнообразия белковых структур и выделению из них тех, которые могут эффективно повлиять на вирус, поэтому в данном проекте также используются методы распределенных вычислений.

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, World Community Grid's FightAIDS@Home project runs a software program called AutoDock developed in Prof. Olson's laboratory. 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, developed 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. From the beginning of this project, World Community Grid has been running a pre-release version of AutoDock4. In August 2007, World Community Grid started running the new publicly available version 4 of AutoDock which is faster, more accurate, can handle flexible target molecules and thus can also be used for protein-protein docking analysis. AutoDock is used in the FightAIDS@Home project on World Community Grid to dock large numbers of different small molecules to HIV protease, so the best molecules can be found computationally, selected and tested in the laboratory for efficacy against the HIV virus. By joining forces together, The Scripps Research Institute, World Community Grid and its growing volunteer force can find better treatments much faster than ever before.

График проекта


Ссылки

ВИЧ 3D

Це повідомлення відредагував Rilian: Sep 8 2010, 11:49

[Rilian]

эксперимент 33 начался, а 32й уже посчитан на 27%

Greetings,

We will be starting experiment 33 soon. These batches start with 13985. At the request from the researchers we will be running these before finishing experiment 32. So you will see a jump from batch 12900 to 13984.

Thanks,
-Uplinger

http://fightaidsathome.scripps.edu/status

[Rilian]

Yes, the rest of Experiment 32 will be postponed until Exp. 33 has finished. Since input files don't really have a shelf-life, we'll just resume Exp. 32 later. Since all the work units are conveniently numbered, this type of thing is easy to implement and keep track of.

We want to bump Exp. 33 to a higher priority in the FAAH queue, because we have not yet performed any virtual screens against our new models of HIV integrase. We have many new results against HIV protease that need to be evaluated in test tubes (which I'll discuss in the next volume of the FAAH Newsletter in June), and we have several more virtual screens against HIV protease that still need to be analyzed. Thus, while we're analyzing and testing the previous screens against HIV protease, we're going to start extending the scope of these FAAH experiments by performing this new type of screen against HIV integrase in Exp. 33. Performing these screens against HIV integrase is a huge milestone for FightAIDS@Home. We want to start searching for these potential new classes of integrase inhibitors as soon as possible.

Thank you all very much for your help,
Alex Perryman, Ph.D.

CODE

http://www.worldcommunitygrid.org/forums/wcg/viewthread_thread,29083#280148

[Rilian]

Experiment 32: 54% Completed

Experiment 33: 3% Completed

Experiment 33 is our first FightAIDS@Home experiment that targets the HIV integrase system.

[Rilian]

9 выпуск новостной рассылки

http://fightaidsathome.scripps.edu/images/FAAH_vol9.pdf

Hi Everybody,

I just posted Volume 9 of the FightAIDS@Home Newsletter to:

http://fightaidsathome.scripps.edu


Cheers,
Alex L. Perryman, Ph.D.

[corsar83]

Project Status, as of August 18, 2010

Experiment 33: 76% Completed

Чуток осталось

[corsar83]

Хоть на сайте у них ещё не обновилось, но судя по заданиям exp33 наверно закончился. Идут задания с недоделаного 32го.

[Ukrkeeper]

сделаю ка я себе бронзу тут

[corsar83]

сделаю ка я себе бронзу тут

Давай уже золото лучше

[Rilian]

Хмм! А с каких пор в проекте кворум = 1 (то есть считается без избыточности) ?

[Ukrkeeper]

бронза

[Tamagoch]

Хмм! А с каких пор в проекте кворум = 1 (то есть считается без избыточности) ?

да вроде об этом года три назад говорилось, а я потом забил на FAH и не помню чем кончилось... или началось

[Rilian]

ВИЧ 3D (добавил в шапку)

http://habrahabr.ru/blogs/i_am_advertising/103774/

[Rilian]

Project Status, as of September 8, 2010

Experiment 33: 93% Completed. Experiment 33 is our first FightAIDS@Home experiment that targets the HIV integrase system.

Experiment 32: 54% Completed

http://fightaidsathome.scripps.edu/status

[corsar83]

Project Status, as of October 11, 2010

Experiment 32: 73% Completed

Experiment 33: 99% Completed

Experiment 34: 0% Completed

Experiment 34 is our second FightAIDS@Home experiment that targets the HIV integrase system

Experiment 34 is our second FightAIDS@Home experiment that targets the HIV integrase system. See the description and the link listed under Experiment 33.

Experiment 34 involves screening the "full National Cancer Institute's (NCI) library" of over 315,000 different compounds against our new dynamic models of the wild type, the G140S/Q148H drug-resistant mutant, and the E92Q/N155H drug-resistant mutant of HIV-1 integrase. We are trying to discover compounds that can bind to and inhibit the active site of the wild type and these two drug-resistant mutants. Since these models all have two magnesium ions in the active site, we are searching for compounds that can inhibit HIV integrase's "strand transfer reaction," which is what the fairly new drug raltegravir (Isentress) does.

We are screening the NCI library of compounds against 4 different snapshots (that is, conformations or 3-D shapes) of HIV integrase: a) the conformation of wild type HIV integrase against which raltegravir docked the best (in the results published in our paper in the Journal of Molecular Biology, March 26, 2010), b) the snapshot of the G140S/Q148H drug-resistant mutant against which raltegravir docked the best in our previous studies, c) the most representative (that is, the most frequently observed) conformation of the E92Q/N155H drug-resistant mutant (according to the results of the QR Factorization method in VMD), and d) the 2nd most representative conformation of the E92Q/N155H drug-resistant mutant of HIV integrase's catalytic core domain.

The best compounds from this virtual screen will be assessed in test tubes, in "strand transfer" assays being developed by our collaborator Dr. Ying-Chuan Lin in Prof. John Elder's lab at TSRI.

This experiment involves faah16,199 - faah17,146.

These calculations will begin in October of 2010.

[Rilian]

Experiment 34: 15% Completed

Experiment 35: 0% Completed

Experiment 35 involves screening the full NCI library of ~ 316,000 compounds against the active site of 8 different versions of HIV protease. Thus, this experiment is similar to Exp. 32, but a different library of compounds is being screened, and one new target has been added. All but two of these target conformations were generated by Dr. Alex L. Perryman's Molecular Dynamics (MD) simulations of 5 different variants of HIV protease. These 8 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. This paper was recently listed as one of the "most read papers" from Chemical Biology and Drug Design this year! 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 8th target has never been used on FightAIDS@Home before. It is a brand new crystal structure from Assoc. Prof. C. David Stout's lab of the chimeric "FIV 6s98S" protease, which was developed by our collaborators Ying-Chuan Lin, Prof. Bruce E. Torbett, and Prof. John H. Elder. A paper on this new crystal structure of FIV 6s98S protease is currently being peer-reviewed. This protease enzyme is "chimeric," because it contains 5 residues from HIV protease that were substituted into the corresponding positions in FIV protease. The 6th residue was also substituted from HIV protease, but it changed into a different residue during serial passage experiments (i.e., during directed evolution studies performed with the presence of different HIV protease drugs). This 6s98S FIV protease has HIV-like drug sensitivity profiles and is a new model system for multi-drug-resistant HIV protease.


This experiment involves faah17,565 - faah20,092.

These calculations will begin in November or December of 2010.