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

 

Figure 1-1. Change Working Directory option.

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

 

Note: The Results folder in the tutorial files contains all the job input/output files.

Figure 1-2. The Open Project panel.

6. Go to File > Open Project.
7. Select the enumeration_tutorial.prjzip file.
8. Click Open.
   • Structures are added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
9. In the Save scratch project dialog box, click OK.

Figure 1-3. Save Project panel.

10. Go to File > Save Project As.
11. Change the File name to enumeration_Cdk2.
12. Click Save.
    • The project is now named enumeration_Cdk2.prj.

Figure 2-1. Selecting the connection point for enumeration.

1. Confirm the Hit 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 and your selection scope is set to Atoms.
2. Select H21 in the purine core.

 

Note: 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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries , please refer to the Glossary of Terms.

3. Go to Tasks > Browse > Enumeration and Ideation > R-Group Enumeration.
   • The Custom R-Group Enumeration panel opens.

Figure 2-2. Running the R-Group Enumeration job.

Note: In this tutorial, you will use the Diverse R-groups library that is packaged along with Maestro. However, any fragment library can be loaded from file or created using the R-Group Creator panel.

4. For R-Group Library, choose Diverse R-groups (43).
5. Change the Job name to R-group_enumeration.
6. Click Run.
   • This job takes a few seconds.
   • A new group R-group_enumeration is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
7. Close the Custom R-Group Enumeration panel.

Figure 2-3. Opening the LigPrep panel.

5. Select the R-group_enumeration group by clicking on the group heading.
6. Go to Tasks > Browse > Ligand Preparation and Library Design > LigPrep (3D Conversion).
   • The LigPrep panel opens.

Figure 2-4. Running the LigPrep job with the default settings.

 

7. For Use structures from, choose Project Table (selected entries).
8. Change Job name to ligprep_enumeration.
9. Click Run.
   • This job takes ~ 1 minute.
   • A banner appears and a new group ligprep_enumeration-out is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
10. Close the LigPrep panel.

Figure 2-5. Opening the Ligand Docking panel.

11. Select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the ligprep_enumeration-out group by clicking on the group heading.
12. Go to Tasks > Browse > Receptor-Based Virtual Screening > Ligand Docking.
    • The Ligand Docking panel opens in the Ligands tab.

Figure 2-6. Running the docking job.

13. For Receptor grid, choose From file.
14. Next to File name, click Browse and choose glide-grid_enumeration.zip from your Working Directorythe location that files are saved.
15. For Use ligands from, select Project Table ( 104 selected).
16. Change the Job name to glide-dock_enumeration.
17. Click Run.
    • This job takes ~3 minutes.
    • A banner appears and a new group glide-dock_enumeration_pv is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
18. Close the Ligand Docking panel.

Figure 2-7. The Ligand-Based ADME/Tox Prediction in Tasks.

19. Select the glide-dock_enumeration_pv group by clicking on the group heading.
20. Go to Tasks > Browse > ADME and Molecular Properties > Ligand-Based ADME/Tox Prediction.
    • The QikProp panel opens.

Figure 2-8. The QikProp panel.

21. For Use structures from, choose Project Table (selected entries).
22. Check the box for Fast mode.
23. Change the job name to ADME-Tox_prediction_enumeration.
24. Click Run.
    • The job takes a few seconds.
    • A banner appears and a new group ADME-Tox_prediction_enumeration-out is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
25. Close the QikProp panel.

Figure 2-9. Opening the Ligand Filtering panel.

13. Select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the ADME-Tox_prediction_enumeration-out group by clicking on the group heading.
14. Go to Tasks > Browse > Ligand Preparation and Library Design > Ligand Filtering.
    • The Ligand filtering panel opens.

Figure 2-10. The Ligand Filtering panel.

15. For Use structures from, choose Project Table (105 selected entries).
16. In the Properties tab, under Available properties, select glide gscore (Impact).
17. For Property, set up the filter criterion r_i_glide_gscore < -8.5.
18. Click Add.
    • The filtering criterion is added.
19. Repeat steps 16-18 for RuleOfFive (QikProp) and PSA (QikProp) and set i_qp_RuleOfFive < 1 and PSA < 140 respectively.
20. Change the Job name to ligfilter_enumeration.  

Note: Ligand filtering allows for a more reasonable number of compounds for later visual inspection.

21. Click the Job settings cog.
    • The Jobs Settings dialog box opens.

Figure 2-11. Running the Ligand Filtering job.

22. Under Output, for Incorporate, choose Append new entries as a new group.
23. Click Run.
    • This job takes a few seconds.
    • A banner appears and a new group ligfilter_enumeration-out is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
    • Only 13 ligands remain following the ligand filtering.
24. Close the Ligand Filtering panel.

Figure 3-1. Opening the Bioisostere Replacement panel.

1. In the ligfilter_enumeration-out group  in the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion, includethe entry is represented in the Workspace, the circle in the In column is blue Hit, from pyridine 2.
2. Go to Tasks > Browse > Enumeration and Ideation > Bioisostere Replacement.
   • The Bioisostere Replacement panel opens.

Figure 3-2. Defining immutable region and running the bioisostere replacement job.

3. In the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed, shift-click to select the entire molecule except for the sulfonamide group.
4. For Use structures from, choose Workspace.
5. For Define immutable region from, select SMARTS and click Get from Workspace Selection.
6. Change the Job name to bioisostere_replacement.
7. Click Run.
   1. This job takes a few seconds.
   2. A banner appears and a new group Hit, from pyridine 2 with 18 entries is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
8. Close the Bioisostere Replacement panel.

Figure 3-3. Selecting Bioisostere Replacement outputs and opening the LigPrep panel.

9. Expand and select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the Hit, from pyridine 2 (18) group by clicking on the group heading.
10. Go to Tasks > Browse > Ligand Preparation and Library Design > LigPrep (3D Conversion).
    1. The LigPrep panel opens.

Figure 3-4. Running the LigPrep job for Bioisostere Replacement outputs.

11. For Use structures from, choose Project Table (18 selected).
12. Change Job name to ligprep_bioisostere_replacement.
13. Click Run.
    1. This job will take ~ 1 minute.
    2. A banner appears and a  new group ligprep_bioisostere_replacement-out is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
14. Close the LigPrep panel.

Figure 3-5. Selecting the LigPrep outputs and opening the Ligand Docking panel.

6. Select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the ligprep_bioisostere_replacement-out group by clicking on the group heading.
7. Go to Tasks > Browse > Receptor-Based Virtual Screening > Ligand Docking.
   • The Ligand Docking panel opens in the Ligands tab.

Figure 3-6. Running the docking job.

8. For Receptor grid, glide-grid_enumeration.zip should already be selected from the previous docking setup.
9. For Use ligands from, choose Project Table (53 selected).
10. Change Job name to glide-dock_bioisostere_replacement.
11. Click Run.
    • This job will take ~2 minutes.
    • A banner appears and a new group glide-dock_bioisostere_replacement_pv is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
12. Close the Ligand Docking panel.

Figure 3-7. Selecting the docking outputs and opening the Ligand Filtering panel..

13. Select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the glide-dock_bioisostere_replacement_pv group by clicking on the group heading.
14. Go to Tasks > Browse > Ligand Preparation and Library Design > Ligand Filtering.
    • The Ligand filtering panel opens.

 

Figure 3-8. Running the Ligand Filtering job.

15. For Use structures from, choose Project Table (selected entries)
    • All previous selections from the panel should still be populated.
16. Leaving the property r_i_glide gscore < -8.5, delete i_qp_RuleOfFive < 1 and PSA < 140 by selecting them and clicking Delete one at a time.
17. Change the Job name to ligfilter_bioisostere_replacement.
18. Click Run.
    • This job takes a few seconds.
    • A new group ligfilter_bioisostere_replacement-out is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
    • Only 21 ligands remain following the ligand filtering.

Figure 3-9. Setting the Workspace to step through the poses.

19. Go to File > Import Structures.
20. Navigate to proteinprep_5NEV folder in your Working Directorythe location that files are saved and select proteinprep_5NEV-out.maegz.
    • A new entry 5NEV – prepared is added to Entriesa 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.
21. Double-click the In circle of 5NEV – prepared.
    • The structure is fixed in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed.
22. Right-click the ligfilter_bioisostere_replacement-out group header and choose Include First Entry (Top Group).

Figure 3-10. Visualizing the poses.

 

 

23. Step through the results using the left and right arrow keys.

Note: Choose a visualization that is most helpful to you. For example, in our case, presets have been applied, interactions are toggled on, labels are hidden, and all the ligands are rendered in ball-and-stick representation. For comparing the ligand poses, it can be helpful to adjust the Auto-fit settings to your preference – if Auto-fit and Ligand are toggled on, the view will zoom to fit each ligand as you switch to its Entry. Turning auto-fit off will keep the view constant as you step through the poses.

24. Once you are done inspecting, right-click the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed and choose Clear Workspace.

Figure 4-1. The Reaction-Based Enumeration option in Enumeration and Ideation in Tasks.

1. Expand CDK2 Inhibitors group in the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
2. Includethe entry is represented in the Workspace, the circle in the In column is blue and select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries CHEMBL296468 from the group.
3. Go to Tasks > Browse > Ligand Enumeration and Ideation > Reaction-Based Enumeration.
   • The Reaction-Based Enumeration panel opens.

Figure 4-2. The Reaction-Based Enumeration panel.

3. For Use compound from, choose Project Table (selected entry).
4. Click Load.
   • The hit structure is added to the sketcher.
5. Set Max depth to 2.

Note: Depth is the longest sequence of steps leading from the target to a starting material. For a linear synthesis, the depth is equal to the number of steps in a reaction, but in a convergent synthesis it can be less.

 

6. Click Display Breakable Bonds.
   • Breakable bonds are highlighted.
7. Click Generate Pathways button.
   • The Review Pathways step is displayed.

Figure 4-3. Adding a filter to the reaction pathways in the Filter Pathways dialog box.

8. Click Filter Options button.
   • The Filter Pathways dialog box opens.
9. Check the box for Reaction Name.
10. In the text box, type thioether.
11. Click OK.
    • A filter is added to the reaction pathways to only show those that include a thioether.

Note: Pathway filtering is helpful for narrowing down the pathfinder results to a more manageable number of pathways.

Figure 4-4. Choosing the reaction pathway for large-scale enumeration.

12. Choose Path 17: thioether-2, amide-coupling-2.
    • The reaction names, as well as the reactants and products, appear under Pathway.
13. Click Define Reactants > button.
    • The Define Reactants step is displayed.

Figure 4-5. Choosing the filter properties.

14. Click SMARTS Filter button.
    • The Filter by SMARTS dialog box opens.
15. From the Read SMARTS Filter button menu, choose From Predefined Filters > REOS.
16. Click Save.
    • Filter is set for all products.

 

Note: You can use the SMARTS Filter to remove any undesired moieties from the enumeration output. You can also use the Property Filter to remove compounds that fall in undesired property-space.

Figure 4-6. Running the large-scale enumeration job.

17. Click Enumerate in the Reaction-Based Enumeration panel.
    • The Enumerate - Job Settings dialog box opens.
18. Change the Job name to enumerate_large_scale.
19. Click Run.
    • This job takes a few seconds.
    • A new group enumerate_large_scale is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
    • 10,000 compounds are generated.

 

Note: Certain reactions will generate multiple products if there are multiple potential products from the given set of reactants. Uncheck Allow multiple products per reaction step in the Reaction-Based Enumeration panel if you would prefer only a single output from each step.

Figure 4-7. Choosing the pathway for core-hopping enumeration.

20. In the Reaction-Based Enumeration panel, click Back twice to return to the Choose Reaction step.

Note: This clears the Pathway filter added in the previous example.

21. Click Generate Pathways.
22. Choose Path 21: suzuki-2, amide_coupling-2.
23. Click Define Reactants > button.

Figure 4-8. Choosing the reactants for the core-hopping enumeration.

Note: To determine which reactants correspond to which portion of the input molecule, hover over the reaction until a tooltip pops up.

24. For Reactant 1 and Reactant 3, choose Original Reactant (1).
    • This will ensure that only the core is varied in each output.
25. Click Enumerate.
    • The Enumerate - Job Settings dialog box opens.

Figure 4-9. Running the core-hopping enumeration job.

26. Change the Job name to enumerate_core-hopping.
27. Click Run.
    • The job takes a few seconds.
    • A new group enumerate_core-hopping is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
    • 180 core hopped compounds are generated.

 

Note: It is normal to get lower than the desired number of products during a core-hopping enumeration since multiple reactive handles are required.

Figure 4-10. Choosing the pathway for R-group enumeration.

28. In the Reaction-Based Enumeration panel, click Back to return to the Review Pathway page.
29. Choose Path 33: amide_coupling-1, thioether-2.
30. Click Define Reactants > button.

 

Figure 4-11. Choosing the reactants for R-group enumeration.

31. For Reactant 2, choose Original Reactant (1).
    • This will ensure that only the R-groups are varied in each of the outputs.

Note: Both of the non-core groups of the input molecule will be enumerated combinatorially.

32. Click Enumerate.
    • The Enumerate - Job Settings dialog box opens.

Figure 4-12. Running the R-group enumeration job.

33. Change the Job name to enumerate_R-group.
34. Click Run.
    • The job takes 4-5 minutes.
    • A new group enumerate_R-group is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
    • The enumeration results in 10,000 unique compounds.

Figure 4-13. Sketching the reaction.

For manual reaction creation in Reaction-Based Enumeration, all R-groups must be drawn explicitly.

35. In the Reactions-Based Enumeration panel, click Back twice to return to the Choose Reaction page.
    • You may need to click OK in the Schrödinger 2D Sketcher - Welcome dialog box.
36. For Get reaction from, choose New Sketch.
37. Sketch a Schiff base condensation reaction.
38. Select the green check mark to clean up.
    • The reaction will appear linear, further modification may be needed.
39. Click Define Reactants.

Figure 4-14. Choosing the reactants for enumeration.

40. For Reactant 1, select Reactant Library and choose amines-prim and click OK.
41. For Reactant 2, select Reactant Library and choose aldehydes and click OK.

 

 

Figure 4-15. The Creating Library from SMARTS dialog box.

Note: To generate new reactant libraries from the Project Table or a file, select Reactant Library and click +New to open the Create Library from SMARTS dialog box.

 

Note: The Create Reactant Library from SMARTS panel can also be accessed by going to Tasks > Browse > Enumeration and Ideation > Create Reactant Library.

Figure 4-16. Choosing filter properties.

42. Click the filter icon next to Reactant 1.
43. Choose Property filter.
44. In the Reactants Tab, check the box for TPSA.
45. For TPSA, set the bounds to 0 and 60.00.
46. Click Save.

 

Figure 4-17. Running the enumeration job.

47. Click Enumerate.
48. Rename the job enumerate_custom_reaction.
49. Click Run.
    • The job takes 10-15 minutes.
    • A new group with 10,000 imine-containing compounds is added to the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
50. Close the Reaction-Based Enumeration panel.

Note: Enumeration jobs with a reactant filter are expected to take longer, as the reactants will need to be pre-filtered before the enumeration can proceed.

Figure 5-1. The Create R-Group Library option in Enumeration and Ideation in Tasks.

1. Expand and select(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 Entries (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the Ligands group in the Entriesa simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion.
2. Go to Tasks > Browse > Enumeration and Ideation > Create R-Group Library.
   • The R-Group Creator panel opens.

 

 

 

 

 

Figure 5-2. Generating R-groups from a set of congeneric ligands.

3. In the Create R Groups tab, choose Analyze R groups from ligands.
4. For Analyze structures from, choose Project Table (selected entries).
5. For Core definition from, choose Maximum Common Substructure.

6. Click Analyze.
   • The R-groups for the set of ligands is defined.  

Note: The Maximum Common Substructure criteria can be set by clicking Settings. Click View Core to see how the core has been defined by the Maximum Common Substructure.

Figure 5-3. Adding R groups to a new library.

7. Click Select All.
8. For Add selected R groups to library, choose New.
   • The New R-group Library dialog box opens.
9. For Library name, type Library_Design.
10. Click OK.

 

Note: New libraries can also be created in the Manage R Groups tab.

 

11. Click Add.
    • The R-groups are added to a new library titled Library_Design.

Figure 5-4. Sketching R-group.

12. Click the Sketch R Groups method.
13. Sketch a thiol.
14. Select the attachment point tool and click on the carbon in your structure.
    • The R-group attachment point is now defined.
15. Name the Fragment thiol.

Figure 5-5. Adding R-group to the library.

16. For Add R group to library choose Library_Design and click Add.
    • The thiol group is added to the Library_Design R-group library.

Figure 5-6. The Manage R Groups tab in the R-Group Creator panel.

17. Go to the Manage R Groups tab.
18. Deselect All.
19. For R-Group Libraries, select Library_Design.

 

Note: In the Manage R Groups tab, you can import R-groups to a library (Import), export an R-group library (Export), create a new R-group library (New), or edit an R-group (More Actions > Edit).