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_interactions.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_Interactions.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_Interactions, click Save
   • The project is now named Ligand_Designer_Interactions.prj

Figure 2-1. Include entries in the Workspace.

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

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: You can uncheck Adjust view when analyzing to retain the view that you currently have when working in the Ligand Designer

Note: The darker blue in the growth space is the solvent exposed region.

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, but you may consider. 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 Protein-Ligand Interactions in the Workspace.

4. Under Display, select Ligand-Receptor Interactions
   • These are inverse pharmacophores on the protein that could potentially interact with the ligand

Figure 2-6. Select the pharmacophore feature on LYS 678 in the Workspace.

5. Select the pharmacophore feature on LYS 678 in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed
   • A pop-up explaining your options appears
6. Click OK

Note: To quickly find the LYS 678 residue you may choose to search for the residue in the Structure Hierarchy.

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. For Scoring Function choose Druglike
3. Click OK
   • 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. Show protein-ligand interactions.

1. In the Structure Hierarchy, search 678
2. Check the box next to LYS 678 to display it in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed
3. Toggle on interactions in the Workspace Toggles

Figure 3-4. Analyze ND-022_1 in the Workspace.

4. Click the right arrow twice in the Ligand Designer
   • ND-022_1 is now 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
   • The radar plot has been updated with the properties of the new compound
   • You can see the hydrogen bond interaction between the hydroxyl group and LYS 678

Figure 3-5. Pose inspection and favoriting.

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

 

Figure 3-6. Sort by MPO.

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

Note: You can also sort by Clashes and Good Interactions

8. 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 3-7. Include ND-022_3.

1. Include ND-022_3 (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

Note: ND-022_3 and ND-022_2 have the same MPO score so either might be on the top of the list

Figure 3-8. 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. If you choose to use the 2DSketcher, remember to be in Draw Mode, indicated by the pencil icon to make edits to the ND-022_2 ligand.

3. Change the indicated hydroxyl group to an amino group using either the 2D sketcher or 3D builder

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

 

Figure 3-9. 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

Note: If you click the arrow on the Predict Pose icon you can switch from using the recommended MCS docking protocol to a minimization protocol.

5. Click the X icon to close the 2D Sketcher

Figure 3-10. View similar purchasable compounds.

1. Include user_designed_ligand_1
2. Click View similar purchasable compounds

Figure 3-11. Predict poses of similar purchasable compounds.

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

Figure 3-12. Favorite the first purchasable compound.

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

Figure 3-13. Save the favorite poses to File.

2. Under Post-Processing, choose Save to File and Favorites
3. Click Save
   • The Save File panel opens

Figure 3-14. Save to your Working Directory.

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