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]

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.