1. Double-click the Materials Science icon
   • (No icon? See Starting Maestro)

Figure 2-1. Change Working Directory option.

2. Go to File > Change Working Directory
3. Find your directory, and click Choose
4. Pre-generated files are included for running jobs or examining output. Download the zip file here: schrodinger.com/sites/default/files/s3/release/current/Tutorials/zip/builders_rgroup_enumeration.zip
5. After downloading the zip file, unzip the contents in your Working Directorythe location where files are saved for ease of access throughout the tutorial

Figure 2-2. Save Project.

6. Go to File > Save Project As
7. Change the File name to r_group_enum, click Save
   • The project is now named r_group_enum.prj

Figure 3-1. Launching the R-Group Creator panel.

First, we need to build our small R-group library for enumeration. The R-Group Creator panel is used to create, edit, and manage R-group libraries

1. Go to Tasks > Materials > Enumeration > R-Group Creator
   • The R-Group Creator panel opens on the 2D sketcher

The 2D sketcher functions like many standard 2D molecular drawing tools. For a complete overview of using the sketcher panel, see the 2D Sketcher Panel documentation

Note: If you will frequently use this panel (or any other), remember that you can click the star in the menu and it will be added as a favorite to your toolbar.

Figure 3-2. Sketching an R-group.

R-groups are created by drawing the functional group of interest and then setting an attachment point. First we will draw a R-H group:

 

2. In the 2D sketcher, click on H in the sketcher toolbar
3. Click anywhere in the sketcher to draw HH  

Note: Use the green check () for a quick clean up of any drawings.

Figure 3-3. Setting the R-group.

4. Click on the New R+ group tool on the bottom left of the panel
5. Click on one of the H atoms and drag it anywhere on the sketcher

Figure 3-4. Creating a new R-group library.

6. In Add R group to library, select New from the drop-down menu
7. Type tutorial_lib as the new R-Group Library name
8. Click OK

Figure 3-5. Adding a created fragment to an R-group library.

9. Change the Fragment name to R-H
10. Click Add to add the created fragment to the R-group library

Figure 3-6. Adding R-CH₃ to the library.

To continue building out our R-group library, tutorial_lib, we will draw a methyl, R-CH₃ group:

 

11. Click on C from the sketcher toolbar
12. Click on the H in the current structure to replace the H with a CH₃ group (designated by just the line and end-point)
13. Change the Fragment name to R-CH3
14. Click Add to add the structure to tutorial_lib

Figure 3-7. Structures of R-Cl, R-t-Bu and R-Ph.

15. Continue to make three more fragments with R-Cl, R-t-Bu and R-Ph groups. See the Figure for guidance. Name and add each of the three R-groups to tutorial_lib. Below are some tips on drawing the three fragments:

 

Note: To clear the sketcher, click Reset Sketcher. You can also continue on with the current structure to create another, related R-group

 

• To draw R-t-Bu (tert-butyl), draw R-CH₃ and at the C atom, draw a line in any direction. Draw two more lines from the same atom in different directions
• Use the eraser tool to clear your sketches

Figure 3-8. Viewing the R-groups in tutorial_lib library.

16. Switch to the Manage R Groups tab and unselect All (3087) and then select the library we just created, tutorial_lib (5)
    • The tutorial_lib library should have five R-groups as shown in the Figure
    • The R-groups listed under R-Group Libraries are the default included libraries, but you may see different options depending on your version of the software and previous use of this panel

 

Note: Several R-group libraries are available by default. You can also import, export or delete from the list of R-group libraries. For a more comprehensive overview of the R-Group Creator panel, see the help documentation

 

17. Close the R-Group Creator panel

Figure 4-1. Importing 2-phenylpyridine structure into the workspace.

1. From the main menu, go to File > Import Structures
2. Navigate to where you downloaded the tutorial files and choose the phenylpyridine.mae file
3. Click Open
   • A new structure titled 2-phenylpyridine is selected(1) the atoms are chosen in the Workspace. These atoms are referred to as "the selection" or "the atom selection". Workspace operations are performed on the selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion and includedthe entry is represented in the Workspace, the circle in the In column is blue in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed

 

Note: Please refer to the Glossary of Terms for the difference between includedthe entry is represented in the Workspace, the circle in the In column is blue and selected(1) the atoms are chosen in the Workspace. These atoms are referred to as "the selection" or "the atom selection". Workspace operations are performed on the selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries

Figure 4-2. Launching Custom R-Group Enumeration panel.

4. Go to Tasks > Materials > Enumeration > Custom R-Group
   • The Custom R-Group Enumeration panel opens with a warning message

 

Note: For a more comprehensive overview of the Custom R-Group Enumeration panel, see the help documentation

 

5. Click OK on the warning message
   • In this tutorial we will select attachment atoms in the following steps, you can however select attachment atoms before launching the panel to avoid the warning message

Figure 4-3. Selecting attachment atoms in the Workspace.

To run the Custom R-Group Enumeration, we first need to select the attachment points on 2-phenylpyridine which we wish to enumerate over

6. In the workspacethe 3D display area in the center of the main window, where molecular structures are displayed, select the indicated atoms, as shown in the Figure, using Ctrl+Click  (Cmd+Click on Mac) for multiple atom selection
   • Make sure to select atoms in the order indicated in the Figure because these attachment positions will correlate to the R-group substituted
   • This panel is interactive with the workspacethe 3D display area in the center of the main window, where molecular structures are displayed, meaning we work with structures in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed while the panel is open

Figure 4-4. Updating R-group table for substitution.

7. In the Custom R-Group Enumeration panel, click Update From Selection
   • The panel now reads in the attachment atoms selected and assigns them to an arbitrary R-group number
   • The panel table shows the attachment Position number, the   number, and the R-Group library to be used for substitution
   • Labels on the structure in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed display the R-group number as well

Figure 4-5. Defining R-groups.

Suppose we want to enumerate over our core structure using both our custom library and a default library. For the purposes of this example, we will allow homo-substitution, i.e. the same R group at each attachment position, for Position 1 & 2 and Position 3 & 4. As each fragment is selected from the library, it is added to all equivalent R-groups, by default

 

8. For Position 1 and Position 2, assign R1 as the R-Group
   • This results in homo-substitution on both positions
9. For the R-Group Library of Position 1, choose tutorial_lib (5)
   • The R-Group Library changes for Position 2 as well
10. For Position 3 and Position 4, assign R2   as the R-Group, and choose Solubilizing_R-groups (33) as the R-Group Library
11. Ensure that your panel matches that which is shown in the Figure

 

Note: The Define R-groups section allows for extremely customizable R-group enumeration. For more information about the options presented here, see the help documentation

Figure 4-6. Allowing substitution on all attachment positions.

We want all four attachment positions to be substituted with our R-group libraries. To ensure that all four positions are being substituted simultaneously, rather than one, two, or three at a time, we must specify substitution across all positions

 

12. In the Custom R-group Enumeration  panel, select Allow partial substitution
13. From the drop down menu, select across all positions and set to Use: 4 of 4

 

Note: The total number of enumerated structures is the raw combination of enumeration points (displayed in the panel as Library size) minus the number of duplicates that are removed due to symmetry, which  results in unique output structures

Figure 4-7. Running R-group enumeration job.

14. For the Job name, input phenylpyridine_enum
15. Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in less than a minute on a CPU host
16. Click Run
    • Once the job is successfully finished, a new phenylpyridine_enum-core-out1 group, with 165 structures, is selected(1) the atoms are chosen in the Workspace. These atoms are referred to as "the selection" or "the atom selection". Workspace operations are performed on the selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion and the first structure is includedthe entry is represented in the Workspace, the circle in the In column is blue in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed
17. Close the Custom R-Group Enumeration panel
    • In general, always close the Custom R-Group Enumeration panel after use. This panel is interactive with the workspacethe 3D display area in the center of the main window, where molecular structures are displayed and leaving it open can therefore be problematic

Figure 5-1. Selecting the enumerated structure library.

1. With the entry group titled phenylpyridine_enum-out (165) selected(1) the atoms are chosen in the Workspace. These atoms are referred to as "the selection" or "the atom selection". Workspace operations are performed on the selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries, go to Tasks > Materials > Tools > Clean Up Complexes
   • The Clean Up Complexes panel opens

 

Note: The Clean Up Complexes panel works on small molecules as well as organometallic complexes. For a more comprehensive overview of the panel, see the help documentation. Or, visit the Help by clicking on on the bottom right.

Figure 5-2. Clean Up Complexes panel.

2. For Use structures from, ensure that Project Table (165 selected entries) is listed; this corresponds with the R-group enumeration group produced in Section 4
3. Click Clean Up
   • The selected structures are minimized in place of the existing group in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion  

Note: Clean Up Complexes panel uses the OPLS_2005 force field for minimization

Figure 5-3. Visualizing a molecule.

Any of the enumerated structures can be visualized in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed by including an entry of interest