Small Molecule Membrane Permeability

Tutorial Created with Software Release: 2023-2
Topics: Hit-to-Lead & Lead Optimization, Small Molecule Drug Discovery
Products Used: Prime

Tutorial files

82 KB
This tutorial is written for use with a 3-button mouse with a scroll wheel.
Words found in the Glossary of Terms are shown like this: Workspacethe 3D display area in the center of the main window, where molecular structures are displayedthe 3D display area in the center of the main window, where molecular structures are displayed

 

Tip: You can hover over a glossary term to display its definition. You can click on an image to expand it in the page.
Abstract:

 

In this tutorial, you will learn how to use the Prime Structure-Based Membrane Permeability Predictor to predict the membrane permeability of a series of small molecules.

 

Tutorial Content

  1. Creating Projects and Importing Structures

  1. Predicting Membrane Permeability

  1. Conclusion and References

  1. Glossary of Terms

1. Creating Projects and Importing Structures

At the start of the session, change the file path to your chosen Working Directorythe location that files are saved in Maestro to make file navigation easier. Each session in Maestro begins with a default Scratch Projecta temporary project in which work is not saved, closing a scratch project removes all current work and begins a new scratch project, which is not saved. A Maestro project stores all your data and has a .prj extension. A project may contain numerous entries corresponding to imported structures, as well as the output of modeling-related tasks. Once a project is created, the project is automatically saved each time a change is made.

Structures can be imported from the PDB directly, or from your Working Directorythe location that files are saved using File > Import Structures, and are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion and Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data. The Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion is located to the left of the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed. The Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data can be accessed by Ctrl+T (Cmd+T) or Window > Project Table if you would like to see an expanded view of your project data.

  1. Double-click the Maestro icon

Figure 1-1. Change Working Directory option.

  1. Go to File > Change Working Directory
  2. Find your directory, and click Choose
  3. 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/membrane_permeability.zip
  4. After downloading the zip file, unzip the contents in your Working Directory for ease of access throughout the tutorial

 

Figure 1-2. Save Project panel.

  1. Click File > Save Project As
  2. Change the File name to Membrane_Permeability, click Save
    • The project is now named Membrane_Permeability.prj

2. Predicting Membrane Permeability

In this section, we will use the Prime Structure-Based Membrane Permeability Predictor to predict the membrane permeability of a set of prepared FDA approved compounds. The Structure-Based Membrane Permeability Predictor is a physics-based tool that calculates an estimated membrane permeability for a ligand structure by comparing the energy-optimized conformations of the ligand in low and high dielectric environments. The Structure-Based Membrane Permeability Predictor generates two different permeability predictions: Membrane dG Insert and Log Perm RRCK. The Membrane dG Insert value is best used when working with a series of similar compounds. The Log Perm RRCK contains an additional volume term added on to the Membrane dG Insert value, and is therefore useful when working with a larger, more diverse series of compounds.  In this tutorial, we will generate dG Membrane Insert values, and plot them against experimental Caco2 permeability data as a validation step.

2.1 Run Membrane Permeability Prediction

Figure 2-1. Select structures in Entry List.

  1. Go to File > Import Structures
  2. Choose adveef.maegz
  3. Click Open
    • Structures are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
  4. In the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion, click on the group header to 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 Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries the group adveef (11)
    • All entries in the group are 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

 

Note: Please see the Glossary of Terms for the distinction 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

When preparing a validation set for the Structure-Based Membrane Permeability Predictor, ensure that your set has a mixture of known permeable and impermeable compounds.

Figure 2-2. Open Membrane Permeability panel.

  1. Go to Tasks > Browse > ADME and Molecular Properties > Physics-Based Membrane Permeability
    • The Membrane Permeability Panel opens

 

 

Figure 2-3. Membrane Permeability panel.

  1. Change Job name to membrane_permeability_adveef
  2. Click Run
    • This job will take 25 minutes on 1 CPU
    • To save time we will look at pregenerated results

2.2 Analyze Membrane Permeability Results

Figure 2-4. Open Project Table.

  1. Go to File > Import Structures
  2. Choose membrane_permeability_adveef-out.maegz
  3. Click Open
    • Structures are in the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
  4. Click the Table button
    • The Project Table opens

The Project Table can also be opened by pressing Ctrl+T (or Cmd+T on Mac)

Figure 2-5. Project Table.

  1. Expand the membrane_permeability_adveef-out group
  2. View the Caco2 Permeabilities in the Project Table 

 

Note: The units for Caco2 Permeability are cm/s

Figure 2-6. Project Table Calculator.

  1. In the Project Table toolbar, click the Calculator button
    • The Property Calculator opens
  2. Fill in the name of the new property as log10_Caco2
  3. Click the Functions button and choose log10
  4. Click the Properties button and choose Caco2
  5. Click )
  6. Click Execute
    • A new column with the log of the Caco2 values is added to the Project Table

 

Figure 2-7. Manage Plots panel.

  1. In the Project Table toolbar, click  the Plot button
    • The Manage Plots panel opens
  2. Click New Scatter Plot

Figure 2-8. Prepare scatter plot.

  1. Choose log10 Caco2 for the x-axis
  2. Choose Membrane dG Insert for the y-axis
  3. Check Best fit line
    • A best fit line is added to the scatter plot
    • The equation of the Best fit line as well as the R2 are now visible
  4. Check the box next to Plot title
    • The plot is now titled Membrane dG Insert vs. log10 Caco2

Figure 2-9. Scatter plot of Membrane dG Insert vs. log10 Caco2.

Note: The permeability is inversely proportional to the Membrane dG Insert.

 

Note: This validation data can be used later in a research project when predicting the membrane permeability of compounds without permeability assay data.

Figure 2-10. Save scatter plot.

  1. In the Scatter Plot panel toolbar, click the Save button (Disk icon)
  2. Next to Save As, change the file name to Membrane dG Insert vs. log10 Caco2
  3. Click Save
    • A copy of the generated scatter plot is now saved in your desired destination

3. Conclusion and References

In this tutorial, the membrane permeability of a set of FDA-approved drugs was predicted and plotted against Caco2 permeability assay results.

For further reading:

 

 

4. Glossary of Terms

cognate ligand - a ligand that is bound to its protein target

Entry List - a simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion

included - the entry is represented in the Workspace, the circle in the In column is blue

incorporated - once a job is finished, output files from the Working Directory are added to the project and shown in the Entry List and Project Table

Project Table - displays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data

Scratch Project - a temporary project in which work is not saved, closing a scratch project removes all current work and begins a new scratch project

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

Working Directory - the location that files are saved

Workspace - the 3D display area in the center of the main window, where molecular structures are displayed