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Monday, June 15

  1. page UClib012 edited A Virtual Library of Dibenzalacetone Derivatives Researchers Andrew SID Lang, Jean-Claude Bra…

    A Virtual Library of Dibenzalacetone Derivatives
    Researchers
    Andrew SID Lang, Jean-Claude Bradley, Matthew J McBride, Anthony J Williams
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    11:43 am
  2. page D-EXP021 edited Docking Imines and Amines Against Tubulin Using Autodock Vina Researchers: Andrew SID Lang, Lor…

    Docking Imines and Amines Against Tubulin Using Autodock Vina
    Researchers: Andrew SID Lang, Lori Fielding, Jesse Patsolic, and Matthew Wilson

    Objective
    To dock library 10 (570 imines and 570 amines) UClib010output against tubulin using vina (version 1.1.1) autodock vina on ORU's cluster.
    Researchers: Andrew SID Lang, Lori Fielding, Jesse Patsolic, and Matthew Wilson
    Procedure
    The SMILES of the imine and the reduced imine columns from the UClib010output spreadsheet were saved as plaintext and saved as a .smi file. This file was used as input to the molconvert program which is part of the JChem and Marvin suites by ChemAxon. The output ( UClib010outputPDB.zip {UClib010outputPDB.zip} ) of the molconvert program yields one .pdb file per SMILE. [Describe the code used for molconvert. JP]
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    11:25 am
  3. page D-EXP020 edited ... Vincent Zoete (Swiss Institute of Bioinformatics) Jean-Claude Bradley (Drexel University) An…
    ...
    Vincent Zoete (Swiss Institute of Bioinformatics)
    Jean-Claude Bradley (Drexel University)
    Andrew SID Lang (Oral
    Objective
    To dock CombiUgi library 7 (15.7 Mb, 117450 Ugi products) against tubulin using SwissDock. All of the compounds in this library have starting materials in abundance in the Bradley lab as of 07/22/2009.
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    11:24 am
  4. page D-EXP022 edited Docking Run 22 Dibenzalacetone Derivatives Against Tubulin Using PaDEL-ADV Researchers: Andre…

    Docking Run 22Dibenzalacetone Derivatives Against Tubulin Using PaDEL-ADV
    Researchers: Andrew SID Lang, Jean-Claude Bradley, Matthew J McBride, and Anthony J Williams
    Docking Run 22
    Objective
    To dock 325 dibenzalacetone derivatives (library 12) against tubulin in order to find replacement candidates for taxol (paclitaxel) that are easier (and cheaper) to synthesize from common starting materials found in abundance in the Bradley lab 2012-07-13.
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    11:24 am
  5. page D-EXP020 edited Docking Ugi Products Against Tubulin Using SwissDock Researchers Aurélien Grosdidier (Swiss I…

    Docking Ugi Products Against Tubulin Using SwissDock
    Researchers
    Aurélien Grosdidier (Swiss Institute of Bioinformatics)
    ...
    SwissDock is a "web service to predict the molecular interactions that may occur between a target protein and a small molecule." The Bradley group investigated using the SwissDock webservice to dock library7 against tubulin, see D-EXP018 for a similar run using vina. Upon investigation and with communication with the developers, it was found that SwissDock is designed for docking a single (or small group of ligands) against a protein and that it would be difficult to use SwissDock as a webservice to run the entire 117,450 compounds of library7. Discussion then followed about a possible collaboration - using the SwissDock technology and expertise at the Swiss Institute of Bioinformatics to dock library7 against tubulin offline at SIB.
    Preliminary Run
    ...
    found here: paclitaxel_1jff.zip. paclitaxel_1jff.zip {paclitaxel_1jff.zip} . While performing
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    11:21 am
  6. page D-EXP018 edited Docking Ugi Products Against Tubulin Using Autodock Vina Researchers: Andrew Lang, Lori Fieldin…

    Docking Ugi Products Against Tubulin Using Autodock Vina
    Researchers: Andrew Lang, Lori Fielding, Jesse Patsolic, and Matthew Wilson
    Objective
    To dock CombiUgi library 7 (15.7 Mb, 117450 Ugi products) against tubulin using autodock vina (version 1.1.1). All of the compounds in this library have starting materials in abundance in the Bradley lab as of 07/22/2009.
    Researchers: Andrew Lang, Lori Fielding, Jesse Patsolic, and Matthew Wilson
    Background
    2D view of the 3 hydrogen bonding sites between paclitaxel and gamma-tubulin (from PDB ligand viewer )
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    11:20 am
  7. page D-EXP018 edited Docking Ugi Products Against Tubulin Using Autodock Vina Objective To dock CombiUgi library 7…

    Docking Ugi Products Against Tubulin Using Autodock Vina
    Objective
    To dock CombiUgi library 7 (15.7 Mb, 117450 Ugi products) against tubulin using autodock vina (version 1.1.1). All of the compounds in this library have starting materials in abundance in the Bradley lab as of 07/22/2009.
    ...
    {pacliHbonds.jpg}
    Procedure
    ...
    saved as receptor.pdbqt. receptor.pdbqt {receptor.pdbqt} . Similarly, the
    ...
    saved as exptaxol.pdb for exptaxol.pdb {exptaxol.pdb} for comparison purposes.
    ...
    saved as conf.txt, conf.txt {conf.txt} , see figure
    receptor = receptor.pdbqt
    center_x = -0.5
    ...
    To dock paclitaxel (CSID 10368587) against tubulin (PDB 1JFF) to verify docking procedure and as a baseline for future results. The 3D structure of paclitaxel was generated from its SMILES (taken from ChemSpider) using molconvertor (part of Marvin 5.5.0.0 in the bin folder) and the following code:
    molconvert -3 pdb taxol.smi -o taxol.pdb
    The taxol.pdb file taxol.pdb {taxol.pdb} file was then
    [So you used only one conformer of paclitaxel? JCB][What's cool about AutoDock Vina is that is automatically detects all rotatable bonds and changes molecular conformation as it docks. AL]
    ---
    ...
    The first (taxolallhydrogens.out_ligand_1.pdb),( taxolallhydrogens.out_ligand_1.pdb {taxolallhydrogens.out_ligand_1.pdb} ), fully protonated,
    molconvert -3 pdb:H taxol.smi -o taxol.pdb
    The second (taxolpolarhydrogens.out_ligand_1.pdb)( taxolpolarhydrogens.out_ligand_1.pdb {taxolpolarhydrogens.out_ligand_1.pdb} ) was created
    ...
    .pdbq files (taxolallhydrogens.out_ligand_1.pdbqt, taxolpolarhydrogens.out_ligand_1.pdbqt)( taxolallhydrogens.out_ligand_1.pdbqt {taxolallhydrogens.out_ligand_1.pdbqt} , taxolpolarhydrogens.out_ligand_1.pdbqt {taxolpolarhydrogens.out_ligand_1.pdbqt} ) shows no
    Docking was performed using all three pdb files (no hydrogens, polar hydrogens, all hydrogens - effectively the same, the pdbq file for all hydrogens only contain polar hydrogens) using PaDel-ADV with the best ligand (all hydrogens) shown below (Affinity: -8.8).
    {ligand1h.docked.png} Blue: docked - Yellow: experimental
    ...
    {dockedblueisexp.png} Figure 2. paclitaxel docked in tubulin. Blue is the experimentally determined docked position, red is the docked position found using AutoDock Vina.
    Second Run
    To dock 10smiles.xlsx from 10smiles.xlsx {10smiles.xlsx} from the first first half of{combiugiLib007-1-58700.csv} of CombiUgi library
    molconvert -3 pdb 10smiles.smi -m -o mol.pdb
    The ten pdb files were then docked against tubulin using the same procedure as the first run.
    ...
    To dock the entirety of library 7 against tubulin. With an average docking time of 2 mins 16 secs per molecule it would take over 6 months to run using a single computer. It may be possible to run the docking in under two days on a cluster currently being built at ORU.
    The First 100 SMILES
    The first 100 100 SMILES from{100smiles.smi} from library 7
    ...
    protonated) - 100 100 pdbs -{First100SMILES.zip} - using the
    molconvert -3 pdb:H 100smiles.smi -m -o mol.pdb
    ...
    hours. The dockingresults.xlsx give dockingresults.xlsx {dockingresults.xlsx} give the top
    Ligand
    Energy
    ...
    [Unfortunately we have never been able to successfully run a Ugi reaction with TOSMIC despite many attempts - not sure why JCB]
    Results of the Full Run
    ...
    58700 results: firstHalfENERGIESwithSMILES.csv. firstHalfENERGIESwithSMILES.csv {20120315firstHalfENERGIESwithSMILES.csv} . The top
    Ligand
    Energy
    ...
    The top ligand - 16562 - is depicted below:
    {c4ccc2ccc1cccc3c1c2c4cc3CCCC(=O)N(c1ccccc1)C(c2cc3c(c1c2cccc1)cccc3)C(=O)NC(S(c1ccc(cc1)C)(=O)=O).gif}
    ...
    the run: secondHalfEnergiesOUTwithSMILES.csv. secondHalfEnergiesOUTwithSMILES.csv {20120408secondHalfEnergiesOUTwithSMILES.csv} .
    The top ten result output were
    Ligand
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    11:20 am
  8. page D-EXP019 edited ... -9.85 A few interesting things to note here. First, it is surprising that the paclitaxel side…
    ...
    -9.85
    A few interesting things to note here. First, it is surprising that the paclitaxel side chain is not always docked in the same orientation as it is in the full paclitaxel molecule. This could mean that the paclitaxel side chain is not as important as assumed in this analysis, though it could also mean that the docking algorithm is missing something important. Secondly, a big concern was that the Ugi products generated from a standard library (like library007) may not be big enough (paclitaxel is comparatively bigger than the Ugi products that have previous been made in the UsefulChem project). By examining the docking visualization it seems that that assumption may not be true and that library007 may contain potential ligands, e.g. 1482 looks big enough, though the acid used here is itself relatively large and may be worth including in the next version of lib007. Thirdly, TOSMIC is showing up again as it did in the second run of D-EXP018. The sulfonyl group seems particularly well suited to sit between the two hydrogen bonding sites at the top.
    Using a Chemist's Brain (Jean-Claude Bradley)
    Log [AL Blue, JCB Red]
    Log
    2011-05-12
    Downloaded and installed Ubuntu using the Ubuntu Windows Installer (AutoGrow 2.0 only runs on linux).
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    11:18 am
  9. page D-EXP021 edited ... Objective To dock library 10 (570 imines and 570 amines) UClib010output against tubulin using…
    ...
    Objective
    To dock library 10 (570 imines and 570 amines) UClib010output against tubulin using vina (version 1.1.1) autodock vina on ORU's cluster.
    Researchers: Jesse Patsolic,Andrew SID Lang, Lori Fielding, Jesse Patsolic, and the ORU undergraduate cluster computer team.Matthew Wilson
    Procedure
    ...
    The output (UClib010outputPDB.zip)( UClib010outputPDB.zip {UClib010outputPDB.zip} ) of the
    The .pbd files were then converted into .pdbqt files which are required for autodock vina. [What program did you use to convert the files? -JP]
    The 1140 .pdbqt files were then run through autodock vina on the ORU cluster computer in about 9 hours. The output from autodock vina was processed into a table giving the best energies for each ligand. [Add vina code. JP]
    ...
    given here: ImineEnergies20120218.csv. ImineEnergies20120218.csv {ImineEnergies20120218.csv} .
    Ligand
    Energy
    ...
    The top Imine is depicted below.
    {C(c2cc3c(c1c2cccc1)cccc3)=Nc1cc(Cl)ccc1.gif}
    ...
    given here: ReducedImineEnergies20120218.csv. ReducedImineEnergies20120218.csv {ReducedImineEnergies20120218.csv} .
    Ligand
    Energy
    (view changes)
    11:14 am
  10. page D-EXP019 edited Rational Drug Design for Tubulin Ligands ... and Andrew SID Lang Objective We will use rat…

    Rational Drug Design for Tubulin Ligands
    ...
    and Andrew SID Lang
    Objective
    We will use rational drug design (both human and bot) to find Ugi products that have the potential to bind to tubulin.
    ...
    Using AutoGrow 2.0 (Andrew Lang)
    First Run
    The scaffold ugi.smi, ugi.smi {ugi.smi} , see image
    ...
    converted to ugifirstrun.pdb using ugifirstrun.pdb {ugifirstrun.pdb} using OpenBabel (GUI)
    {ugi.gif} core Ugi scaffold - ugi.smi
    AutoGrow was executed using the following command from the AutoGrow_2_0_4/bin directory
    ...
    number of generations: 8 //8
    After 6 of 8 generations it was noticed that AutoGrow was only growing and mutating the original Ugi core structure about the single explicit hydrogen in the ugifirstrun.pdb file. This is not very useful from a combiugi viewpoint so the final two rounds were aborted. For interest, we present the two best (most negative affinity) ligands from round 6 - neither compound was found in ChemSpider:
    ligand1.out_ligand_1.pdb (SMILES:{ligand1.out_ligand_1.pdb} (SMILES: C(=O)(N1C[NH2]c2[nH]c(nc2C(=NO)NN1c1nc(=O)c2c(nc(cn2)C(=O)O)[nH]1)Oc1c2nc(cnc2nc(N)n1)C(=O)O)C(C)(C)N(C(=O)C)C -
    ...
    -10.9)
    ligand3.out_ligand_1.pdb (SMILES:{ligand3.out_ligand_1.pdb} (SMILES: c1nc(c(n1Nc1nc2c(nc1C(=O)O)[nH]c(nc2=O)N1N(C(=O)C(C)(C)N(C(=O)C)C)C[NH2]c2[nH]c(nc2C(=NO)N1)Oc1c2nc(cnc2nc(N)n1)C(=O)O)N)C#N -
    The following images are the 2D images rendered using depict, with both SMILES causing the following warning:
    WARNING: Atom has unusual valence 4 (normal 5) (dy_rmbord)
    ...
    The file created had lines that ended in +0, e.g.
    HETATM 1 C UNK 0 -1.456 -5.067 0.269 0.00 0.00 C+0
    ...
    removed from ugi.pdb by ugi.pdb {ugi.pdb} by using search
    /usr/java/jre1.6.0_25/bin/java Main -run_mode Execute -parm_file default.prm
    but with a slightly different default.prm file - I reduced the maximum number of atoms to 100 (from 150) and added instructions not to link to the polar hydrogen atom connected to the nitrogen (ironically the only hydrogen that was connected to in the first run):
    ...
    affinity
    SMILES
    generation_8_ligand37.pdb {generation_8_ligand37.pdb}
    -11.9
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C(=C(C[C@]1(C)C(=O)NCOC1=Nc4c(cccc4)N(C1)O)N2n1c(C)c(cn1)C#N)C(=S)NC(=S)N3)c1cc(=O)[nH]n2c1nnc2
    generation_8_ligand1.pdb {generation_8_ligand1.pdb}
    -11.6
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C(=C(C[C@]1(C)C(=O)NCOC1=Nc4c(cccc4)N(C1)O)N2)C(=S)NC(=S)N3)c1cc(=O)[nH]n2c1nnc2
    generation_8_ligand2.pdb {generation_8_ligand2.pdb}
    -11.5
    C(C(=O)N(Cc1c(C)c2c(cc1)cn[nH]2)C(C)(C)C(=O)N[C@H](OC1=Nc2c(cccc2)N(C1)O)n1c(=O)ccc2c1C(=O)[C@@H](C=C2O)O)[C@@H]1C(=O)c2ccc(=O)[nH]c2C(=O)[C@@H]1O
    generation_8_ligand28.pdb {generation_8_ligand28.pdb}
    -11.5
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C4=C([C@H]([C@]1(C)C(=O)NCn1ncc5c(=N)sc(nc15)S)N1c5c(SC)nnc(c5N[C@H]1[S]=C4NC(=S)N3)S)N2)c1cc(=O)[nH]n2c1nnc2
    generation_8_ligand34.pdb {generation_8_ligand34.pdb}
    -11.5
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C(=C(C[C@]1(C)C(=O)N[C@@H](n1ncc4c(=N)sc(nc14)S)c1cc(=O)n([nH]c1=O)c1[nH]nnn1)N2)C(=S)NC(=S)N3)c1cc(=O)[nH]n2c1nnc2
    generation_8_ligand29.pdb {generation_8_ligand29.pdb}
    -11.4
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C(=C(C[C@]1(C)C(=O)NCn1ncc4c(=N)sc(nc14)S)N2)C(=S)NC(=S)N3)c1cc(=O)[nH]n2c1nnc2Sc1c2cn[nH]c2nnn1
    generation_8_ligand25.pdb {generation_8_ligand25.pdb}
    -11.3
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C(=C(C[C@]1(C)C(=O)N[C@@H](n1ncc4c(=N)sc(nc14)S)c1c(C)[nH]c(n1)N(=O)=O)N2)C(=S)NC(=S)N3)c1cc(=O)[nH]n2c1nnc2
    generation_8_ligand3.pdb {generation_8_ligand3.pdb}
    -11.3
    C(C(=O)N1CCC(=O)[C@H]([C@@H](O)c2ccco2)N2[C@@H]3C(=C([C@@H]([C@]1(C)C(=O)NCOC1=Nc4c(cccc4)N(C1)O)Nc1nc(c4ncsc4n1)O)N2)C(=S)NC(=S)N3)c1cc(=O)[nH]n2c1nnc2
    generation_8_ligand5.pdb {generation_8_ligand5.pdb}
    -11.2
    C(C(=O)N(C)[C@](C)(CSc1nc2c(nc(n2n2c3c(c[nH]n3)c(=O)nc2S[C@@H]2c3ncnc(c3N=N2)O)O)c(n1)O)C(=O)NCOC1=Nc2c(cccc2)N(C1)O)[C@@H]1C(=O)c2ccc(=O)[nH]c2C(=O)[C@@H]1O
    generation_8_ligand4.pdb {generation_8_ligand4.pdb}
    -11.2
    C(C(=O)N(CNC(=O)c1c[nH]nc1NN)C(C)(C)C(=O)N[C@H](OC1=Nc2c(cccc2)N(C1)O)n1c(=O)ccc2c1C(=O)[C@@H](C=C2O)O)[C@@H]1C(=O)c2ccc(=O)[nH]c2C(=O)[C@@H]1O
    ...
    aldehyde: [R2]-C=O
    isocyanide: [R3]-N#C
    ...
    The generated Lib008 Lib008 Ugi Product SMILES were{Lib008UgiProductSMILES.txt} were then converted
    molconvert -3 pdb:H lib008.smi -m -o lib8ligand.pdb
    Results
    ...
    run). The results were results {D-Exp019VinaResultsLib008.xlsx} were analysed and the top top 21 ligands were{D-Exp019Top21VinaResultsLib008.xlsx} were docked locally
    ...
    and the top top 7 docked ligands (pdb{DExp019Top7CombinedScoreLigandsDocked.zip} (pdb - zip)
    {DExp019AllThreeDocked.png} Top Three Docked Ligands - Note the paclitaxel acid is not at the top for the last two ligands
    ID
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    11:13 am

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