Generate Degrader Ternary Complexes Panel (Beta)

This panel is used to create an ensemble of ternary complexes for bifunctional degraders. Given the structure of a target bound to warhead 1 and the structure of a ligase bound to warhead 2, this panel generates an ensemble of possible ternary complexes between the target, ligase and one or more PROTAC molecules that contain warhead 1 and warhead 2 (or that are very similar to those warheads).

To open this panel, Clickclick the Tasks button and browse to Degraders and Macrocycles → Generate Degrader Complexes (Beta)Clickclick the Tasks button and browse to Other Applications → Generate Degrader Complexes (Beta)

For background information, see this webinar.

Explore additional options by running $SCHRODINGER/run -FROM psp protein_degrader_sampler.py –h from the command line.

 

  • Features
  • Additional Resources

Generate Degrader Ternary Complexes Panel Features

 

Inputs section

    Ligase complex menu

    Choose a ligase complex. From the menu, select a Workspace Entry, a Selected Entry, or choose From File to browse. When a structure is loaded from a File, the file path will be displayed to the right of the menu. When a structure is loaded from the Project Table (via Workspace Entry or Selected Entry), the entry title will be displayed to the right of the menu.

    Target complex menu

    Choose a target complex. From the menu, select a Workspace Entry, a Selected Entry, or choose From File to browse. When a structure is loaded from a File, the file path will be displayed to the right of the menu. When a structure is loaded from the Project Table (via Workspace Entry or Selected Entry), the entry title will be displayed to the right of the menu.

    Degraders option and menu

    Choose the options for Full molecules or Linkers only. Click the Browse button to select full degrader molecules from supported file types.
    Full molecules accepts one or more 3D files (.mae or .maegz) or one or more 2D files (SDF), with prepared full degraders containing warhead 1 and 2.
    Linkers only
      The target is always attached to the first * in the SMILES string, and the ligase to the second one.
      Once a linker has been loaded, a menu becomes available for specifying warhead attachment atoms.
      Click Specify Attachments to open the menu to indicate the attachment points for the two warheads by specifying the atom number within the entry. Select the Pick option to initiate atom selection in Workspace, and the corresponding atom number will be displayed in the menu.
      Note: Only hydrogen atoms may be used.
      Click the Attach linker in both directions option to apply the linker bidirectionally, resulting in twice as many output poses.
Options section
    Sampling protocol and Steps menu and settings

    Choose a sampling protocol from the menu: MCMM, CONFGEN, CONFGEN_RDKIT, or Presampled. If Presampled if selected, a browse button becomes available to select a pre-sampled file.

    To specify the number of Steps, enter a numerical value into the corresponding text box or adjust the value using the arrow buttons. The default value is 10,000. Note: This option is unavailable if the sampling protocol is selected Presampled.

    Maximum clashes text box

    To specify the number of Maximum clashes permitted, enter a numerical value into the corresponding text box or adjust the value using the arrow buttons. The default value is 5.

    Save Conformational Sampling option

    Enable the option to save conformational sampling. The file is written as an output when the job is complete.

Output section
    Max poses to return text box

    To specify the number of Max poses to return that are permitted, enter a numerical value into the corresponding text box or adjust the value using the arrow buttons. The default value is 50.

    Score with PIPER option

    If this option is enabled, the returned poses are ranked based on the PIPER pose energy. The default is the Energy property from the sampling.

    Refine complexes (interface and linker only) option and text box

    Enable this option to refine the ternary complexes using Prime. If enabled, this option also enables the Top poses that will be selected for refinement via the text box, where a numerical value can be entered and adjusted using the arrow buttons.

    The target is always attached to the first * in the smiles string, and the ligase to the second one.

Tutorials

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