Project Status, as of November 13, 2009

Experiment 31: 0% Completed

Experiment 31 involves screening the Otava library of approximately 360,000 "building blocks" against the "exo site" on the side surfaces of HIV protease (i.e., the putative allosteric inhibitor sites). This experiment will dock these fragments against the exo sites of 7 different targets, which include 5 carefully-selected snapshots from previous Molecular Dynamics simulations of the V82F/I84V multi-drug-resistant mutant "super bug." The other targets correspond to the two new fragment-bound crystal structures of HIV protease that were produced by our collaborator, Prof. C. David Stout at TSRI. These two new structures from Prof. Stout were also targeted in Experiments 25-28 and 30.

This experiment involves faah8972 - faah11491.

These calculations will begin soon.

Experiment 30: 66% Completed

Like Experiment 29, Experiment 30 also uses the "Asinex" library of over 360,000 different compounds in a virtual screen against HIV protease. But in this experiment, the Asinex compounds are being docked against the allosteric inhibitor site (that is, the "exo site" on the sides of HIV protease). In addition, this experiment targets two new fragment-bound crystal structures of protease that were produced by our collaborator, Prof. C. David Stout at TSRI. These two new structures from Prof. Stout were also targeted in Experiments 25-28.

This experiment involves faah8234 - faah8971.

These calculations began 10/05/2009.

Experiment 29: 100% Completed

This experiment involves docking a huge library of compounds against the active site of six of our new models of HIV protease (which are a subset of the targets being used in Experiments 25-27). These six targets are the outputs of the equilibration phase of six different Molecular Dynamics simulations (hence the "mdEq" part of the work units' names). The six different types of HIV protease that we are docking compounds against in Exp. 29 include the "Model6Xapo," which is a drug-resistant "super bug" with 6 different mutations. Our collaborator, Prof. Dave 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. This Model6Xapo has semi-open flaps (that is, the two double-arrows that point towards the center of the molecule and form a roof over the active site have opened up). We've been working with the IBM members of the FAAH 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 exactly what we mean when we say "semi-open flaps."

Another new model that is being targeted in Exp. 29 is the wild type HIV protease from 1HHP.pdb. We consider this model to be interesting, because the flaps were fairly open, but then they closed again. But this time, they closed down in the opposite arrangement/they "switched handedness" (that is, the flap that is normally in the front is now in the back). Having this different conformation of the flaps might allow us to fish out new types of interesting compounds for subsequent examination in the "test tube."

We included models of a multi-drug-resistant "super bug" with mutations at V82F/I84V and another "super bug" with mutations at I62V/V82A/I84V/L90M.

We are targeting a model of the protease molecule from "HIV-1c," as well. HIV-1c is the subtype, or group of 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 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. In addition, studying these versions of HIV protease can also help us learn how to defeat the "super bugs" we find here in the USA.

This experiment is the first one in which we are using the "Asinex" library of over 360,000 different compounds in our virtual screens against HIV protease.

This experiment involves faah6022-faah8233.

These calculations began 4/23/2009 and ended 10/20/2009.

Experiment 28: 100% Completed

This experiment utilizes the same set of brand new crystal structures and new models of HIV protease that are being used in Experiments 25-27. See the description of Experiment 25 for the details about these new targets. In experiment 28, we are AutoDocking these compounds against the active site of different variants of HIV protease.

This experiment incorporates a library of ligands that we just started using: the ChemBridge building blocks library. The library of "building blocks" from ChemBridge contains many small fragments that were derived from larger compounds. Using these small fragments, or building blocks, should help us cover a larger amount of structural diversity (i.e., of "chemical space") within each experiment. Thus, this library should help us find new hits in a more efficient way.

This experiment involves faah5710-6021.

These calculations began 4/05/2009 and finished 4/24/2009.

Experiment 27: 100% Completed

This experiment utilizes the same set of brand new crystal structures and new models of HIV protease that are being used in Experiments 25 and 26. See the description of Experiment 25 for the details about these new targets. In experiment 27, we are targeting the exo site on the sides of HIV protease.

This experiment incorporates a library of ligands that we have never used before. We recently downloaded and reformatted the "ChemBridge building blocks library" of ~ 12,000 models of compounds from "ZINC," (which stands for Zinc Is Not Commercial). See the paragraph below for a few details about ZINC. The library of "building blocks" from ChemBridge contains many small fragments that were derived from larger compounds. Using these small fragments, or building blocks, should help us cover a larger amount of structural diversity (i.e., of "chemical space") within each experiment. Thus, this library should help us find new hits in a more efficient way.

This experiment involves faah5398-5709.

These calculations began 3/26/2009 and finished 4/09/2009.

Experiment 26: 100% Completed

Similar to Experiment 25, this experiment also involves screening the NCI's "DTP library of moderately active compounds" against several brand new structures and new models of HIV protease. But in this experiment, we are docking the potential inhibitors against the active site, instead of the exo site. See the description of Experiment 25 for the details regarding the new structures and models that we are targeting.

This experiment involves faah5320-5397.

These calculations began 3/16/2009 and ended on 3/31/2009.

Experiment 25: 100% Completed

This experiment involves screening the NCI's "DTP library of moderately active compounds" against the exo site of several brand new structures and new models of HIV-1b protease. (See the description of "Experiment 21" for more details about this DTP library.) This experiment targets the potential allosteric inhibitor site (i.e., the "exo site") on the sides of HIV protease. The new structures utilized in this experiment are based on brand new, currently unpublished x-ray crystallographic structures from our collaborator, Prof. David Stout.

The new models of HIV protease that are also included in this experiment were harvested from Molecular Dynamics simulations recently performed by Dr. Alex L. Perryman. We harvested the equilibrated structures from the beginnings of our new MD simulations on several different multi-drug-resistant mutants of HIV-1b protease (i.e., several different "super bugs" against which the current drugs no longer work well.) We also included models of HIV-1c protease ("1c" is the HIV subtype, or group of strains, that are most common in Asia) and HIV-2 protease ("HIV-2" is the predominant subtype in Africa). "HIV-1b" is the subtype of HIV most commonly found in the U.S. and in Europe. The current anti-AIDS drugs were all designed and optimized against HIV-1b, but the FightAIDS@Home project is devoted to trying to help all patients with HIV throughout the world.

This experiment involves faah5224-5319.

These calculations began on 03/03/2009 and ended on 3/31/2009.

Experiment 24: 100% Completed

Similar to Experiment 12, this experiment performed by Dr. Ruth Huey involves HIV protease "cross-docking" (i.e., this is a test of the new AutoDock code and the new scoring function that involves docking all the known HIV protease inhibitors against 100 different crystal structures of HIV protease).

This experiment involved faah4998-5017.

These calculations began 08/11/2008 and finished 08/31/2008.

Experiment 23: 100% Completed

Similar to Experiments 19 and 19a, this Relaxed Complex experiment involves docking the different FDA-approved HIV protease inhibitors (and a few compounds still in development) against the active site of 2,000 different snapshots of HIV-1b protease that were harvested from a Molecular Dynamics simulation. However, this experiment involves docking these reference compounds against conformations of the V82F/I84V multi-drug resistant "super bug" of HIV protease. We'll compare the performance of these compounds in this experiment versus their calculated affinities from Experiments 19 and 19a.

The reference compounds used in Experiments 19, 19a, and 23 include the FDA-approved drugs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, while the compounds in development include AB2, AB3, JE-2147, KNI-272, TL3, and TMC-126.

This experiment involves faah4726-4791.

These calculations began 12/01/2008, and they finished 02/19/2009.

Experiment 22: 100% Completed

This Relaxed Complex experiment is very similar to Experiment 21, but this time the "DTP" library is being docked against the potential allosteric inhibitor site on the peripheral surface of HIV protease (i.e., the "exo" site), instead of docking them against the active site. These compounds are also being docked against the same "QR-selected" subset of conformations from the V82F/I84V multi-drug-resistant mutant of HIV protease. For a description of the QR method and a few citations, see the description of Experiment 21.

Experiment 22 involves faah4417-4622 and faah5018-5223.

These calculations began 10/18/2008, and they ended 03/05/2009.

Experiment 21: 100% Completed

This Relaxed Complex experiment is testing both a new library of ligands and a new method for selecting the snapshots of the target from MD against which to dock these compounds. The first 1/3 of ligands from the NCI's "DTP" library of compounds is being tested now, while we prepare the files that describe the other 2/3 of this library of compounds.

**Update 07/31/2008** All 3/3 of this library have now been prepared by Dr. Stefano Forli. The other 2/3 of this experiment have been submitted.

These compounds were "moderately active" in cell-based assays at the NCI, but noone knows which targets these bind to or how they are able to inhibit them. These compounds are being docked against the active site of a "QR-selected" subset of conformations harvested from Molecular Dynamics simulations of the V82F/I84V multi-drug-resistant mutant of HIV protease (i.e., a target from one of the most drug-resistant "super bugs" of HIV). The Structure QR method is a new tool for selecting a structurally diverse, non-redundant set of conformations from a group of different structures that have similar sequences.

We thank John Eargle of the Luthey-Schulten lab at UIUC for helping us learn how to apply this method. For more info. on QR, see P. O'Donoghue and Z. Luthey-Schulten; Evolutionary profiles derived from the QR factorization of multiple structural alignments gives an economy of information; J. Mol. Biol., 346, 875-894, (2005). See also MultiSeq of VMD: Elijah Roberts, John Eargle, Dan Wright, and Zaida Luthey-Schulten; MultiSeq: Unifying sequence and structure data for evolutionary analysis; BMC Bioinformatics, 7:382 (2006).

This experiment involves faah4314-4416, 4623-4725, and 4792-4997.

These calculations began 08/28/2008, and they finished 2/19/2009.

Experiment 20: 100% Completed

This Relaxed Complex experiment is similar to Experiment 16, but different run parameters are being used during the docking and several different protocols for preparing the input files of these compounds are being tested (such as using different protocols to calculate the charges on the atoms within each ligand, using different "atom types" to describe the ligands, and using different protocols for minimizing the structures of the ligands). Thus, this experiment will also allow us to investigate the best way(s) for preparing ligands that will be used in subsequent Relaxed Complex experiments.

This experiment involves faah4202-4313.

These calculations began 06/08/2008, and they ended on 9/30/2008.

Experiment 19a: 100% Completed

This Relaxed Complex experiment involves docking the different FDA-approved HIV protease inhibitors (and a few compounds still in development) against the active site of 2,000 different snapshots of the wild type HIV-1b protease that were harvested from the same Molecular Dynamics simulation discussed above in Exp. 19. These calculations will provide a base-line against which to compare the performance of the compounds used in Experiment 19. Different protocols for preparing the input files of these current drugs were used (such as using different protocols to calculate the charges on the atoms within each ligand, using different "atom types" to describe the ligands, and using different protocols for minimizing the structures of the ligands). Thus, this experiment will also allow us to investigate the best way(s) for preparing ligands that will be used in subsequent Relaxed Complex experiments. The reference compounds used in Experiment 19a include the FDA-approved drugs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, while the compounds in development include AB2, AB3, JE-2147, KNI-272, TL3, and TMC-126.

This experiment involved faah4070-4201.

These calculations began 05/26/2008 and finished 08/19/2008.

Experiment 19: 100% Completed

This experiment is similar to Exp. 13, but different run parameters are being used (for example, 2 point cross-over is being used, while Exp. 13 used the arithmetic crossover protocol in the genetic algorithm used in the docking calculations; a new and improved version of the AutoDock code is being used, as well). Exp. 19 is a Relaxed Complex experiment of the "9 false negatives" from the NCI Diversity Set. These 9 compounds did not dock well in previous experiments (by Max Chang and Dr. Lindy Lindstrom) that targeted different crystal structures of HIV protease, but they did display some activity in an experimental assay against HIV protease. Different versions of these 9 ligands and of a few reference compounds are being docked against the active site in 2,000 different snapshots of the wild type protease that were harvested from Dr. Alex Perryman's previously-published Molecular Dynamics simulations (i.e., the cover article of the April, 2004, issue of Protein Science).

The reference compounds used in Experiment 19 include the FDA-approved drugs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, while the compounds in development include AB2, AB3, JE-2147, KNI-272, TL3, and TMC-126.

To view some of the recent results from the Relaxed Complex experiments on these reference compounds, see the graph with part of Indinavir's Relaxed Complex "trajectory" or the comparison of AB2's versus AB3's RC "trajectories" at the bottom of this page.

This experiment involved faah4000-4069.

These calculations began 05/02/2008 and finished 06/14/2008.