User:Michael F. Nagle/Notebook/Chem 571/2013/01/29

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Description

1. Launching Maestro and Storing Chosen Flavanoid Structures

  • Launch Maestro from terminal:
    • select directory from terminal: press F5: type $maestro
  • Draw Structures on Maestro
    • Edit -> build -> fragments: when finished create project
    • Workspace ->Create Project
  • Optimize molecule to lower energy state
    • Use Impact Energy Minimizer under Application: change host to zorro
    • Export Structures


2. Generate Fingerprints

  • Launch Canvas from terminal:
    • select directory from terminal: press F5: type $canvas
  • Import molecule structures
    • Applications ->binary fingerprints -> molprint2D
    • Run Program
  • Click Edit -> Add Column and name column (ex. Flavanoids)
    • Right-click header of new column and choose "Set Property Value"
      • Type in a temporary name for the set of reference compounds in the modal fingerprint (ex. modal row fingerprint row)
      • Click OK
  • Click Structure ->Change Structure Name Property
    • Select "Flavanoid" as the source property and ensure "Store current as new property" is selected.
      • This merges all the fingerprints into a single fingerprint
  • Click File ->Export
    • Choose the fingerprint file type (.fp) and assign a name (ex. flavanoid_fingerprints.fp)
      • In the next Export Options dialog which opens, ensure the desired fingerprint is selected, remove all properties from the "selected properties" list, uncheck the option to Export Canvas UIDs and click OK
  • Restore original names of all structures by clicking Structure -> Change Structure Name Property
    • select "Original Title as source property, uncheck the option to store the current name as original title 2 and click ok
    • now you may delete the "Flavanoid" column
  • Open a command line terminal window -> go to the directory where the fingerprint is:
    • type: $SCHRODINGER/utilities/canvasFPCombine -i flavanoid_fingerprints.fp -o flavanoid.modal.fp


3. Add fingerprint to zorro database

  • Open in canvas the molecules to be screened (zorro database)
  • Add fingerprint to database
    • import flavanoid_modal
    • click allow duplicate mappings -> click OK


4. Screen Fingerprint

  • Applications -> Similarity/Distance screen->select fingerprint
    • Tainimoto similarity
    • Choose fingerprint column
  • After screening select wanted compounds ~15000
    • export

5. Prepare for docking

  • Import fingerprint regions to Maestro
  • Use ZINC database to download PDB structures of target proteins
  • Import PDB structures
  • Prepare the proteins:
    • Workflows ->protein prep
      • Add H+
      • uncheck delete waters
      • click preprocess
      • Then click refine tab:
        • change pH 7.4
        • Optimize: then minimize hydrogens

6. Superimpose Proteins

  • Tools ->protein structure alignment
    • all->align
    • remove H2O and nonpolar H using sidebar
  • Use the protein with the higher resolution
  • When protein is chosen -> click "show ribbon" to see ribbon structure of protein

7. Docking

  • Prepare: remove water molecules
    • Duplicate the project
    • Click Delete->molecules->manually click H2O
  • Make a grid of the docking region
    • Application ->glide ->Receptor Grid Generation
      • Define ligand: click it
      • Click site tab -> center on ligand -> change dock ligands to length 15 angstroms
    • Click Start
  • Name grid glide-grid_KRM
    • check the zorro box
  • When run is finished check to redock:
    • Isolate ligand
    • Click Applications -> ligand docking
      • load grid (zip file) ->use project table
      • Ensure zorro is selected -> replace 1 with the *-> select 1 test
      • Click Start
    • Import pv.file
      • check new ligand with previous ligand
  • Compare flavanoids
    • Superimpose flavanoids to ensure similar fit
  • Screen database:
    • Aplication ->Glide->ligand docking->open file->click start


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