Isosteric Matching Panel

Find alternative scaffolds for a template ligand by defining a scaffold, replacing the scaffold with a set of alternatives, and scoring the ligands based on their shape similarity to the template, with optional application of excluded volumes and flexible alignment (conformational adjustment).

To open this panel: click the Tasks button and browse to Lead Optimization → Isosteric Matching.

  • Using
  • Features
  • Additional Resources

Using the Isosteric Matching Panel

Isosteric matching (shape-based core hopping) is useful when you want the cores to be similar to the template core. The similarity can be defined simply in terms of volume overlap, or can involve weighting different regions of the volume overlap, or requiring that certain atom types or pharmacophore types match. You might, for example, start with a natural substrate and want to make a drug-like molecule that is similar. As well as matching the template shape, you can filter out structures that occupy forbidden regions of space (excluded volumes) that might be occupied by the receptor. For information on setting up excluded volumes, see Setting Up Excluded Volumes for Isosteric Matching.

To write out the input file and a script for running the job from the command line, click the arrow next to the Settings button and choose Write. For information on command usage and options, see ch_isosteric_matching_driver Command Help.

Isosteric Matching Panel Features

Set Up Job tab

Set up the input for the job in this tab. Once the input is set up, you can use the Job toolbar to start the job.

Specify template section

Specify the template to which the new cores will be matched. The basic task in this section is to identify the side chains (R groups) that you want to keep on the template molecule, while substituting the rest of the template with scaffolds from other molecules. The bonds to these side chains are called attachment bonds.

Input Structure button

Import a structure into Maestro and display it in the Workspace. Opens the Import Structure file selector, in which you can choose a Maestro file or a combinatorial definition file (from CombiGlide). You can choose a template that was exported from a previous run, for example.

Define Template option

When you have a structure in the Workspace, select this option to design the template for core hopping.

Click the bonds to the side chains that you want to keep as part of the new structures. The bonds are marked with an arrow pointing towards the side chain. Multiple clicks on the first bond change the direction of the arrow, then clear the bond selection, then select it again. For the subsequent bonds, multiple clicks select and deselect the bond.

If the structure already has attachment bonds marked, you can select this option to change them; if it does not, you must select this option to mark bonds before you can find new cores.

When you have finished selecting bonds, deselect this option to exit template definition.

Export Template button

Export the template to a Maestro file. The file includes the core definition information.

Specify Cores section

Specify the cores to use for the job.

Use structures from option menu

Choose the source of the cores for the job.

  • Project Table (selected entries)—Use the entries that are currently selected in the Project Table.
  • File—Use the structures from the specified file. When this option is selected, the Input file text box and Browse button are activated. Click Browse and navigate to the file you want to use. The file name is displayed in the text box when you click Open in the file selector. You can also enter the file name in the text box.
Input file text box and Browse button

Specify the file containing the structures for the potential new cores. Click Browse to navigate to the file, which can be a Maestro file (.mae*) or an SQLite database (.sqlite). The file name is displayed in the Input file text box.

In the file selector, under Look in, there is an item for the standard core libraries in the installation, labeled Schrodinger Cores. The libraries are SQLite databases. You can also use the corefinder Command Help utility to generate a database from your own structures.

Job Options section

In this section you can specify options and settings for input to the job.

Minimum ShapeSim score box

Set the minimum shape similarity between the core and the template cores for a core to be accepted as a match. Cores whose score do not meet this threshold are rejected.

Use Phase excluded-volume file option and Browse button

Select this option to use excluded volumes from Phase to filter out new core molecules that occupy these excluded volumes. Click Browse to navigate to and select the file, which must have the extension .xvol or .ev. See Setting Up Excluded Volumes for Isosteric Matching for information on creating these files.

Flexibly align new potential cores option

When aligning the new potential cores, use conformational changes to improve the alignment.

Database Filters button

Open the Database Filters Dialog Box, in which you can filter the cores. The dialog box allows you to set the minimum and maximum numbers of heavy atoms, hydrogen-bond acceptors, hydrogen-bond donors, nitrogen and oxygen atoms, chiral centers, and number of occurrences, and also specify the element, charge, and number of attachments for the attachment atoms on the new cores.

Advanced button

Open the Isosteric Matching Advanced Options Dialog Box, to control the parameters of the search.

Visualize Results tab

In this tab you can visualize the results of a core hopping run. The run can be any run - it is not restricted to the run just done. The template is fixed in the Workspace and the new cores are selected in the Project Table so you can step through them and see how they align to the template. The attachment bonds are marked with arrows for the template and the new structures. The arrows and the carbon atoms are colored green for the template, and red for the new structure.

Import section

Import or identify the template and set up the Workspace for visualization. The setup involves fixing the template in the Workspace, applying the visualization style, and displaying the first result. Setup is done automatically when you import the template from a file or select it in the Project Table.

Obtain data from option menu

Choose the source of the results. The choices are Run just done, Earlier run (file), and Earlier run (Project Table). The choice determines which button is displayed to the right for loading the template and applying the style.

Select Template in Job Directory button

This button is available if you choose Earlier run (file) from the Obtain data from option menu. Click this button to navigate to the directory that contains the run, and choose the template structure file.

Set Up Workspace button

This button is available if you choose Run just done from the Obtain data from option menu. Click this button to fix the template in the Workspace, select the new entries in the Project Table, show the first result, and apply the color schemes.

Select Entries in Project Table button

This button is available if you choose Earlier run (Project Table) from the Obtain data from option menu. If you do not have the template selected in the Project Table, you are prompted to select an entry when you click this button.

Visualize section

Select options for visualization of the results in this section.

Show in Workspace option

Select the Template option if you want to show the template structure in the Workspace.

Show only isosteric-matching properties in the Project Table option

Select this option to hide all properties in the Project Table other than those that are relevant to isosteric matching.These properties include the sidechain rmsd, the number of linkers (nlinkers), and the largest number of linkers used in any side chain (linker sc max).

Job toolbar

Manage job submission and settings. See Job Toolbar for a description of this toolbar.

The Job Settings button opens the Isosteric Matching - Job Settings Dialog Box, where you can make settings for running the job.

Status bar

The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.

Use the Reset button to reset the panel to its default settings and clear any data from the panel. You can also reset the panel from the Job toolbar.

The status bar also contains the Help button , which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.

Quick Reference Sheets

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