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/ligand_designer_wm.zip
5. After downloading the zip file, unzip the contents in your Working Directorythe location that files are saved for ease of access throughout the tutorial  

Figure 1-2. Open Project panel.

6. Go to File > Open Project and choose Ligand_Designer_WM.prjzip
7. Click Open
   • Structures are shown in the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
   • A 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

Figure 1-3. Save Project panel.

8. Go to File > Save Project As
9. Change the File name to Ligand_Designer_WM, click Save
   • The project is now named Ligand_Designer_WM.prj

Figure 2-1. Include entries in the Workspace.

1. Use Ctrl+click to include ACC Receptor, ND-022, and watermap_ND-022 in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed

Note: Recent advances in the Ligand Designer now allow two receptors to be used at once

Figure 2-2. Ligand Designer in Lead Optimization.

2. Go to Tasks > Browse > Lead Optimization > Ligand Designer
   • The Ligand Designer panel opens

Figure 2-3. Analyze Workspace.

3. Click Analyze Workspace
   • New entries are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion in the Ligand Designer group
   • The Workspacethe 3D display area in the center of the main window, where molecular structures are displayed now has just a single ligand and a cloud surrounding it to represent the growth space

Note: Uncheck Adjust view when analyzing to retain the previous view in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed

Note: The darker blue growth space indicates the region is solvent exposes

Figure 2-4. Select a Primary Receptor.

Note: You can also design ligands with two receptors. One is the primary receptor, for which you want to optimize binding. The other can be a receptor for which you want to minimize off-target effects, for example; or a conformer of the primary receptor, for which you want to optimize binding for both receptors.

The example shown in Figure 2-4 shows two identical receptors. In this case, the choice of which is primary is irrelevant.

Figure 2-5. Visualize Displaceable waters in the Workspace.

4. Under Display, select Displaceable Waters
   • These are high energy waters, are previously determined by WaterMap
5. Click the Workflows dropdown, and select Displace Unstable Water

Note: The protein structure has been undisplayed using the protein quick-select and the style panel

Figure 2-6. Select high energy water in the Workspace.

6. Select the marked high energy water by the phenyl-group of ND-022
   • Vectors appear from different possible attachment points
   • A pop-up explaining your options appears

Figure 2-7. Select attachment point.

7. Select the marked attachment point
   • A pop-up up appears

Figure 2-8. Launch the enumeration.

8. Click Enumerate
   • The enumeration job is launched
   • New entries are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion after they are successfully docked
   • You can follow the status of the job with the status bar at the bottom of the Ligand Designer panel

Figure 3-1. Radar plot.

1. Next to Multi-Parameter Optimization, click the cog
   • A pop-up appears

Note: You can customize the relative importance of various parameters, the expected value distribution, and the thresholds across that distribution.

Figure 3-2. Customize MPO.

Note: You may need to expand the table to see all of the columns

2. Change the Threshold for PSA to 120 by double clicking
3. Click OK
   • The Scoring function is changed to “Custom”
   • The radar plot in the Ligand Designer is now populated based on the updated MPO
   • The MPO value is a geometric mean of the score assigned to each of the parameters (weighted by the specified weights)

Figure 3-3. Analyze ND-022_1 in the Workspace.

1. Click the right arrow in the Ligand Designer
   • ND-022_1 is now included in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed
   • The radar plot has been updated with the properties of the new compound

Figure 3-4. Pose inspection and favoriting.

2. Continue going through the poses with the right arrow in the Ligand Designer
3. When you see a pose you like, click the star icon to add it to your favorites

Figure 3-5. Sort by MPO.

4. Under Post-Processing, click the dropdown and select Sort by MPO

Note: You can also sort by Clashes and Good Interactions

5. Click Sort
   • Compounds in the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion are now sorted by MPO score

Figure 3-6. Include ND-022_1.

1. Include ND-022_36 (the enumerated compound with the best MPO score), in the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion

Figure 3-7. 2D Sketcher in the Ligand Designer.

2. For Display, choose 2D/3D Editing

Note: You can make edits either directly in the sketcher or in the Workspace using the 3D Builder. Any change you make in the Workspace with the 3D builder will be mirrored in the 2D sketcher

3. Make a change to ND-022_36. Here we have converted an alkane into an alkene. Use predicted properties while creating your analog. If you choose to use the 2DSketcher, make sure you are in Draw Mode indicated by the pencil icon.

Note: The properties under the sketcher are synced with the sketcher and will update automatically before your compound is docked.

Figure 3-8. Predict Pose.

4. Click Predict Pose
   • The Pose is predicted and added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
5. Includethe entry is represented in the Workspace, the circle in the In column is blue the new Entry in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed
6. Click the X icon to close the 2D Sketcher

Figure 3-9. View similar purchasable compounds.

1. Include the user-designed_ligand in the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
2. Click View similar purchasable compounds

Note: If you do not have an FPsim-GPU license you will not be able to access this panel

Figure 3-10. Predict poses of similar purchasable compounds

Note: The Purchasable Compounds panel performs a fingerprint-based search against over a billion purchasable compounds and returns the 10 most similar to the compound that is included in the Workspace

3. Click Predict Poses
   • The poses for the 10 most similar compounds are predicted and added to the Entry List

Figure 3-11. Favorite the first purchasable compound.

1. Click the star icon to add the top purchasable compound to favorites

Figure 3-12. Save the favorite poses to File.

2. Under Post-Processing, click the dropdown and choose Save to File
3. Click the dropdown that says All, and choose Favorites
4. Click Save
   • The Save File panel opens

Figure 3-13. Save to your Working Directory.

5. For File name, type ND-022_036_enum_favorite
6. Click Save
   • The favorite compounds are saved to your Working Directorythe location that files are saved