News. Volume 7: April 14, 2009

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FightAIDS@Home News Volume 7: April 14, 2009 The FightAIDS@Home Project uses the volunteered computer power of the World Community Grid to test candidate drug compounds against the variations

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

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

1 News Volume 7: April 14, 2009 The 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 means that wedges allosteric can conformational (which inhibitors disrupt the changes that

2 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 2

3 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 3

4 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 process. 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 4

5 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. 5

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.

6 We've been working with the IBM members of the 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 6

7 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. 7

We could not perform this much research without your help.

multi-drug-resistant super bugs of HIV and for helping us improve the

against other diseases. Prof. Arthur J. Olson Dr. Alex L. Perryman Dr.

8 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 ripps.edu/ 8

News. Volume 8: November 2, 2009

News. Volume 8: November 2, 2009 FightAIDS@Home News Volume 8: November 2, 2009 The FightAIDS@Home Project uses the volunteered computing power of the World Community Grid to test candidate compounds against the variations (or mutants