Project Status, as of Sep. 23, 2008

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: 0% 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.

Experiment 22: 0% 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.

Experiment 21: 21% 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.

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.

Experiment 18: 55% Completed--Has Been Halted

NCI Diversity Set (1900) vs. 500 conformations from the first 5 ns of MD on the V82F/I84V drug-resistant "super-bug" of HIV protease. These results will be compared to those from Experiments 10, 11, and a future experiment, in order to help test and improve the methods and tools that can be used in drug design research against any target of interest.

This experiment involves faah3202-3702.

This experiment is now "on hold." It was halted before its completion, because an error was discovered in the code. The massive number of calculations that you perform for us helped us discover a serious error, and now we have made it much harder to accidentally mis-compile the code. In addition, we have now created new methods for checking the quality of the results. Thus, by helping us improve our code and our protocols, this little setback will help our research in the long-run, and it will help the research that over 4,000 other labs perform with the AutoDock code. We will repeat this experiment (or something very similar to it) with the WCG's new version of the AutoDock code, which is now up-and-running.

Experiment 17: 88% Completed--Has Been Halted

Relaxed Complex Method of Several Compounds, Their Fragments & Several Derivatives versus the Exo site of snapshots from MD of the V82F/I84V drug-resistant "super-bug" of HIV protease (from 1D4S.pdb).

This experiment involves faah3145-3201.

This experiment is now "on hold." It was halted before its completion, because an error was discovered in the code. The massive number of calculations that you perform for us helped us discover a serious error, and now we have made it much harder to accidentally mis-compile the code. In addition, we have now created new methods for checking the quality of the results. Thus, by helping us improve our code and our protocols, this little setback will help our research in the long-run, and it will help the research that over 4,000 other labs perform with the AutoDock code. We will repeat this experiment (or something very similar to it) with the WCG's new version of the AutoDock code, which is now up-and-running.

Experiment 16: 100% Completed

Relaxed Complex Method of Several Compounds, Their Fragments & Several Derivatives versus the Exo site of snapshots from MD of Wild Type 1KZK

Experiment 15: 100% completed

Relaxed Complex Method of the NCI Diversity Set versus the Exo site of snapshots from MD of Mutant 1D4S

Experiment 14: 100% Completed

Relaxed Complex Method of the NCI Diversity Set versus the Exo site of snapshots from MD of Wild Type 1KZK

Experiment 13: 100% Completed

Relaxed Complex Method of the 9 false negatives from the full NCI Diversity Set

Experiment 12: 100% completed

HIV protease cross-docking (i.e., this is a test of the new AutoDock code and the new scoring function). This experiment helps us test and improve the tools that we use in these calculations (and that thousands of other labs use in their drug design research against other diseases). This experiment involves faah2695-2714.

Experiment 11: 100% Completed

NCI Diversity Set (1900) vs. 500 conformations from the first 5 ns of MD on wild type HIV protease

Experiment 10: 100% Completed

This was Dr. Alex Perryman's first experiment on FAAH. The NCI Diversity Set of compounds was docked against 7 "interesting" snapshots of the V82F/I84V multi-drug-resistant "super bug" of HIV protease. These snapshots were deemed "interesting," since they seemed to be very useful in Dr. Perryman's previous Relaxed Complex experiments. That is, these compounds displayed some of the lowest (i.e., best) Free Energies of Binding against the inhibitor JE-2147, and these 7 conformations helped resolve the compounds that bound well from those that did not bind (in previous computational experiments).

Experiment 9: 100% Completed

The "consensus" wild type crystal (2BPW.pdb) was used to screen Max Chang's version of the "DTP library of moderately-active compounds" from the NCI. For details on why this wild type protease is considered a "consensus wt," follow the link on the previous page to the FAAH paper published in the Journal of Chemical Information and Modelling.

Experiment 8b: 100% Completed

Drugs et al. vs. SCWRL-modeled mutants (no H2O) with flexible sidechains

Experiment 8a: 100% Completed

Drugs et al. vs. SCWRL-modeled mutants (no H2O) (rigid)

Experiment 7b2: 100% Completed

x2AZ8 vs ZINC Fragment Library (exo site)

Experiment 7b1: 100% Completed

x2AZ8 vs ZINC Fragment Library (active site)

Experiment 7a2: 100% Completed

x2BPW vs ZINC Fragment Library (exo site)

Experiment 7a1.1: 100% Completed

Fragment Library vs 2BPW (Active Site)

Experiment 6a, 6b, 6c, 6d: 100% Completed

NCI vs. 1MEU, 2BPZ, 2BPW, & 2AZ8

Experiment 5: 100% Completed

BindingDB vs. HIV Protease, with and without Active Site Water Molecule

Experiment 4: 100% Completed

NCI Diversity Set vs. HIV PR Monomer

Experiment 3: 100% Completed

Testing Sidechain Motion in HIV Protease Cross Dockings

Experiment 2: 100% Completed

ChemBridge (500,000) vs. Wild Type HIV Protease (1)

Top Hits from Stage 1 vs. Mutant HIV Protease Panel (270)

NCI Diversity Set (1,900) vs. Monomeric HIV Protease (20)

Experiment 1b: 100% Completed

NCI Set (230,000) vs. Wild Type HIV Protease (1)

Experiment 1a: 100% Completed

NCI Diversity Set (1,900) vs. Mutant HIV Protease Panel (270)