WCG - FightAIDS@home

Medikamentensuche durch "Docking"-Simulationen (Mapping Cancer Markers, FightAIDS@home, Smash Childhood Cancer, ...)
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CurlyM
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Re: WCG - FightAIDS@home

#13 Ungelesener Beitrag von CurlyM » 18.04.2009 14:14

Der FightAIDS@home Newsletter Volume 7 ist da!!! :roll2:
http://fightaidsathome.scripps.edu/images/FAAH_vol7.pdf
The FightAIDS@Home Project uses the volunteered computer power of the World Community Grid to test candidate drug compounds against the variations (or ?mutants?) of HIV that can arise and cause drug resistance. FightAIDS@Home has identified new HIV protease active site inhibitors that have been shown to work fairly well in the test tube and which are now being further developed by our chemist collaborators. In addition, several compounds were recently discovered to be potential candidates for a novel binding site on one of the most multi-drugresistant "super bugs" of HIV protease, the ?V82F/I84V? mutant.

Results of a recent experiment seem very promising
In Experiment 22, which you helped us perform on the WCG, our new version of the NCI?s ?DTP library of moderately active compounds? was screened against the theoretical ?exo site? on the sides of HIV protease. The exo site is highlighted by a yellow box in the image below. This experiment is searching for compounds that have the potential to be developed into
?flexibility wedges? (which means ?allosteric inhibitors? that can disrupt the conformational changes that HIV protease must undergo in order to function). If the computations running on your computers can help us discover and develop these flexibility wedges, they will represent a completely new class of anti-AIDS drugs.

We docked these ?DTP? compounds against the exo site of 103 different conformations, or shapes, that represent the structural diversity that the V82F/I84V mutant displayed in our previous Molecular Dynamics simulations. These MD simulations are like an intricate, precise version of atomic pinball combined with ?Newton?s cradle?, in which models of the atomic structure of a protein are built at a nanometer scale, placed into a simulated bath of water molecules and salt, and then gently heated up to room temperature. As the MD simulation proceeds, the warm water allows the protein to wiggle, jiggle, breathe, and dance around. Recording snapshots of the different poses it samples during this dance gives us an idea about the different shapes, motions, and flexibilities that a drug target like HIV protease can display when it?s in a test tube or in a patient. In our experiments on FightAIDS@Home, we try to discover new compounds that are either (1) ok at binding to and blocking certain key regions of many of these different shapes or (2) compounds that are pretty good at binding to and blocking a few of these different shapes. In the lingo of the pharmaceutical industry, these potentially
interesting compounds are called ?hits.?

The compounds that perform the best in your calculations on the WCG are re-tested on our local computers at TSRI and analyzed extensively. From the first half of Experiment 22 (that is, from the first 3,000 models of compounds that represent the different states that 1,000 of the 2,000 compounds in this library can display), twenty compounds already looked interesting and were quickly re-tested. Twelve modeled compounds successfully passed the virtual, or in silico, retesting process. We tried to order all twelve of these compounds from the NIH, but they were out of five of them. Consequently, we were only able to order seven of these compounds from the ?DTP library of moderately active compounds?. We?ll try to order the other five again later, after we give the NIH some time to replenish their stocks. Wish us luck. In addition, we will soon try a few different protocols for sorting and analyzing these computational results, in order to fish out more compounds that might be interesting. We will most likely want to re-test and then order additional compounds from the first half of Experiment 22. And we?ll probably find other new compounds that seem interesting amongst the other half of the library of potential inhibitors that were part of this experiment. Please stay tuned and try to be patient.
The calculated binding mode of one of these compounds that we just ordered is shown above as a set of green balls on the side of the red HIV protease ?super bug.? To preserve our ability to publish these results later, we intentionally obscured the details of the identity of this compound. If we can?t publish results in scientific journals, then we risk losing our grant money from the NIH, and then we lose our jobs. We have to be sure to follow the well-established rules
of the research process.

Once these twelve compounds arrive, the compounds will then be investigated in vitro by our collaborators in Prof. John Elder?s lab and in Prof. Bruce Torbett?s lab at TSRI, which means that their potency for blocking the ability of HIV protease to work will be characterized in test tubes, with real copies of the HIV protease enzyme that is used by this ?super bug?. If any of these compounds are proven to work well in the test tube, then we will perform another round of modeling studies on the computer. This time we will modify, extend, and ?chemically decorate? these compounds, in order to try to create new compounds that are even better at binding to and blocking the ability of HIV protease to function. The newly-designed compounds that perform well in this round of virtual experiments will then be created by our collaborators in the synthetic chemistry labs of Prof. M.G. Finn and Prof. Valery Fokin (who used to be a member of Prof. Barry Sharpless?s lab). The real versions of these new compounds will then be examined in the test tube in another round of assays performed by the Elder lab. If the new compounds are proven to be very good at binding to and blocking the function of HIV protease, then these compounds will advance to the next stage of the design and evaluation process, called ?lead
optimization.? Lead optimization refers to the process in which ?medicinal chemists? make many small changes to a promising compound and to the rest of the stuff that goes into a pill with it. They make these changes in order to try to increase the compound?s ability to dissolve well in the stomach (without being destroyed by the stomach acid), enter the bloodstream, distribute through the body to reach the infected cells, enter the infected cells, and then bind to and block
the target, without accidentally also binding to important human proteins, which can cause toxic side effects. As you can see in the diagram on the left, discovering compounds and developing them into drugs is a very long, difficult, iterative rocess. And a compound can?t be called an actual ?drug? until it then passes all three phases of ?clinical trials? in humans.

Experiments Currently Crunching on your Computers
We just started screening the ?Asinex? library of over 360,000 different compounds against the ?active site? of six of the new models of HIV protease from our MD simulations. The active site is the hollow central region of the protease enzyme. It?s the mouth that HIV protease uses when it chops up the newly-synthesized viral polypeptide chains, which then allows the individual viral components to separate, fold up into their mature shapes, and then start infecting other cells. The current anti-HIV protease drugs all bind to and block the active site (which is highlighted by a yellow box in the next two images in this volume).
We are screening the Asinex library against these targets to try to find compounds that can bind to and block the function of the different shapes and motions that the ?super bugs? display. The six different types of HIV protease molecules that we are docking compounds against in this experiment include the "Model6Xapo," which is a drug-resistant "super bug" with 6 different mutations in each half of the protease enzyme.
Our collaborator, Prof. David Stout, figured out the structure of this 6X mutant. The "apo" part of the name indicates that this mutant protease molecule did not have a substrate or drug present when its structure was solved. The conformation of this ?super bug? we are targeting has ?semiopen flaps?. In other words, the two double-arrows that normally point towards the center of the protease molecule (on your screen-saver) and grasp each other tightly to form a roof over the
active site have now started to open up in this version of our new target.

We've been working with the IBM members of the FightAIDS@Home team to update the graphics on your screen-savers. We've sent them new graphics to use, and they've already started testing them. Soon, you will be able to see whenever the calculations on your computer involve a docking target that has these "semi-open flaps." For now, look at the image on the previous page.
Targeting these protease molecules with ?semi-open? flap conformations might allow us to fish out new types of interesting compounds for subsequent examination in the "test tube." Building on the research recently published by Prof. Heather Carlson?s lab, we are hoping to find new compounds that can bind to the region between the tip of a flap and the top of the wall that forms the side of the active site. In the image below, this region is highlighted by a red crosshair.
This particular region only appears to be accessible when the flaps are opening up (or when they are already fully open). When the flaps are closed, this region is completely hidden.
In this experiment, we also included new models of a multi-drug-resistant "super bug" with mutations at V82F/I84V and another "super bug" with mutations at I62V/V82A/I84V/L90M. In addition, we are targeting our new model of the protease molecule from "HIV-1c?. HIV-1c is the subtype, or group of HIV strains, that is most commonly found in Asia. We are also targeting a model of "HIV-2" protease with semi-open flaps. HIV2 is the group of strains that are most commonly found in Africa. The current anti-AIDS drugs were developed and optimized against "HIV-1b," which is the subtype most commonly found in Europe and the USA. But some of these current anti-HIV protease drugs do not work as well against even the wild type strains that are found in other regions (let alone their "super bugs"). Since we are not controlled by the desire to
make profit, we are devoting some of our research efforts to the groups of HIV strains that affect the often-neglected patients in Africa and Asia. As an added bonus, studying these other versions of HIV protease can also help us learn new strategies to defeat the "super bugs" we find here in the USA.

The Personnel Touch
Our system administrator, Dr. Alex Gillet, has joined Illumina Inc. as a Software Engineer. He has been replaced by Dr. Sargis Dallakyan. Sargis now makes sure that our computers in Prof. Olson?s lab all work well and that data transmission between our lab and the WCG proceeds smoothly. Sargis Dallakyan is from the former Soviet republic of Armenia. He finished Yerevan State University and got his Ph.D. degree in Theoretical Physics from Yerevan Physics Institute. He then did post-doctoral research at the European Center for Research and Advanced Training in Scientific Computing, at the University of Arizona and at California State University, Northridge. Sargis joined Prof. Olson's Molecular Graphics Lab in 2005 as a Research Programmer and he has been a Lead Developer for ?PMV?, the Python Molecular Viewer.

The images displayed in this volume were made with PMV. A few images were created by Dr. Alex Perryman, and the rest were made by Dr. Stefano Forli. Prof. Art Olson created the flowchart diagram.

We could not perform this much research without your help. Thank you very much for helping us advance the fight against multi-drug-resistant ?super bugs? of HIV and for helping us improve the tools and techniques that many other labs use in their own research against other diseases.

Prof. Arthur J. Olson
Dr. Alex L. Perryman
Dr. Stefano Forli
Dr. Sargis Dallakyan
Dr. Garrett M. Morris
http://fightaidsathome.scripps.edu/

harald.schuette

Re: WCG - FightAIDS@home

#14 Ungelesener Beitrag von harald.schuette » 18.04.2009 17:44

prima - richtig ausführlich. :wink:
und jetzt bitte noch einmal auf deutsch für jene minderheit, die vor 35 jahren nicht in der schule beim englisch aufgepasst haben. :oops:

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Michael H.W. Weber
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Re: WCG - FightAIDS@home

#15 Ungelesener Beitrag von Michael H.W. Weber » 19.04.2009 08:17

Uff, das ist nicht wenig Arbeit. Mal den ersten Absatz vorknöpfen:
The FightAIDS@Home Project uses the volunteered computer power of the World Community Grid to test candidate drug compounds against the variations (or ?mutants?) of HIV that can arise and cause drug resistance. FightAIDS@Home has identified new HIV protease active site inhibitors that have been shown to work fairly well in the test tube and which are now being further developed by our chemist collaborators. In addition, several compounds were recently discovered to be potential candidates for a novel binding site on one of the most multi-drugresistant "super bugs" of HIV protease, the ?V82F/I84V? mutant.
Das FightAIDS@Home Projekt benutzt die freiwillig zur Verfügung gestellte Rechenkraft des World Community Grids, um Substanzen (dpotentielle Kandidaten für Medikamente) gegen Variationen (oder Mutationen) von HIV zu testen, die zur Resistenz des Virus gegen die üblichen Medikamente führen können. FightAIDS@Home hat neue Inhibitoren gefunden, die das aktive Zentrum der HIV Protease inhibieren und die im Reagenzglas auch halbwegs vernünftig funktionieren. Diese Inhibitoren werden nun von unseren Kooperationspartnern (Chemikern) weiterentwickelt. Zusätzlich wurden kürzlich mehrere potentielle Kandidaten entdeckt, die an eine neue Bindestelle der multiresistentesten HIV Proteasenvariante (also der V82F/I84V Mutante) andocken.

Michael.

P.S.: V82F/I84V Mutante bedeutet, daß in dieser medikamenteresistenten HIV Proteasevariante an Position 82 die Aminosäure Valin gegen Phenylalanin und an Position 84 das Isoleucin gegen Valin ersetzt ist. Solche Mutanten entstehen, wenn z.B. ein Medikament eingesetzt wird, daß für seine Wirksamkeit die Originalpositionen erfordert. Durch zufällige Fehler bei der Reproduktion der Virenpartikel entstehen dann Varianten, die in den betreffenden Aminosäurepositionen verändert sind. Da das Medikament diese Viren nicht mehr blockieren kann, vermehren sich diese Mutanten, sodaß es im Organismus zu einer kompletten Umstellung der Population auf die neue HIV Variante kommt. Also ganz simple Evolution...
Fördern, kooperieren und konstruieren statt fordern, konkurrieren und konsumieren.

http://signature.statseb.fr I: Kaputte Seite A
http://signature.statseb.fr II: Kaputte Seite B

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CurlyM
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Re: WCG - FightAIDS@home

#16 Ungelesener Beitrag von CurlyM » 13.11.2009 19:02

Der FightAIDS@home Newsletter Volume 8 ist da!!! :roll2:
http://fightaidsathome.scripps.edu/images/FAAHvol8.pdf

In dem Newsletter finden sich folgende Überschriften:
- FightAIDS@Home results were included in a recent publication
- Follow-up on Experiment 22: the best-ranked compounds from the "DTP library" failed the second round of "wet lab" experiments
- New approach: Fragment-based virtual screens vs. the exo site yield promising results
- Potential significance of the development of allosteric inhibitors of HIV protease
- The American Recovery and Reinvestment Act of 2009 (ARRA) provides stimulus for our future FAAH experiments
- Assisting the computer-aided drug discovery community

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X1900AIW
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Re: WCG - FightAIDS@home

#17 Ungelesener Beitrag von X1900AIW » 19.07.2013 12:37

Es gib eine neue Applikation, diejenige welche m.W. bereits im Beta-Test gelaufen ist:

Siehe WCG-Forum AD Vina calculations are now running on FightAIDS@Home (=Zitatquelle, Hervorhebung von mir), vom 18.07.2013.
  • "(...) Today, the IBM World Community Grid team just finished grid-enabling a new approach to these calculations that will help us expand the scale and increase the throughput by orders of magnitude. In all of the previous ( ~ 45 million) docking calculations performed for FAAH, we used the program called ?AutoDock,? which the Olson lab has been developing for a couple of decades. See: http://autodock.scripps.edu and http://mgl.scripps.edu for more information. Starting today, we can now perform virtual screens on FAAH that use a different, newer type of software called ?AutoDock Vina? (or ?AD Vina?). See http://vina.scripps.edu for additional details. AD Vina was also created and developed in the Olson lab, but it was written from scratch by Oleg Trott (see http://www.olegtrott.com/ ). AD Vina uses a different search algorithm and a different scoring function than AutoDock, and AD Vina is generally 10 to a 100 times faster. In many systems (and when dealing with highly flexible compounds) AD Vina is more accurate than AutoDock, but in other systems AutoDock is more accurate. They both provide complementary types of data that we will sometimes want to compare, to help us advance the search for new candidate compounds that could potentially be developed into new drugs to fight multi-drug-resistant mutant ?superbugs? of HIV. Consequently, in some FightAIDS@Home experiments on World Community Grid, we will be using the new AD Vina, in other experiments we will use AutoDock 4.2, and in some experiments we will use both types of software. Volunteers won't have to make any decisions, and the main difference you might notice is a new FAAH screen saver when it runs on Vina. (...)
  • With your help and continued support, I bet we can perform over 1 billion AD Vina calculations on FightAIDS@Home in less than a year. Let's make it happen!"
Zusammenkommen ist ein Beginn, Zusammenbleiben ist ein Fortschritt, Zusammenarbeiten ist ein Erfolg.
Henry Ford

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Gromobir
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Re: WCG - FightAIDS@home

#18 Ungelesener Beitrag von Gromobir » 21.11.2013 17:34

Nun gibt es auch den Newsletter Nummer 12: http://fightaidsathome.scripps.edu/images/FAAHvol12.pdf
Schön, dass es langsam aber stetig voran geht. :)

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