AutoDesigner - Linker Design Panel
Set up and run an AutoDesigner workflow to explore linker chemical space with docking-based scoring and filtering.
To display this panel- click the Tasks button and browse to De Novo Design → AutoDesigner Linker Design
- Overview
- Using
- Features
- Additional Resources
Overview
AutoDesigner Linker Design is a de novo design workflow that explores linker chemical space to generate novel compounds that connect two fixed R-groups with docking-based scoring and filtering. The workflow keeps two R-groups constant while replacing the linker that connects them with novel linker structures. The generated compounds can be used as input for Active-Learning FEP+.
Linker Design is useful when the key pharmacophoric elements of a molecule are at either end and the connecting linker region needs to be optimized for properties such as potency, selectivity, or physicochemical balance. It requires a high-quality protein structure and is target-agnostic.
The Linker Design algorithm uses a multistage search approach:
A combination of the built-in linker library and optional user-provided linkers is used as the starting set of linker structures.
The two fixed R-groups are connected through each linker at all possible attachment positions.
The output is filtered using the Target Property Space, a complexity filter, SMARTS-based substructure filter, excluded SMARTS filter, LigPrep filter, Glide docking filter, and any optional additional filters.
Linker Design uses a filtering cascade that includes over 1,500 proprietary SMARTS patterns to capture basic chemistry rules, chemical stability, and medicinal chemistry liabilities. The substructure-based filtering is automatically adjusted each run to ensure the starting ligand passes the substructure filter.
Using the AutoDesigner - Linker Design Panel
To set up a Linker Design job:
Prepare the Glide input files: a grid file, a docking input file with core constraints, and a reference ligand file.
In the Setup tab, load a starting ligand and click Edit in 2D sketcher to define the two R-groups to keep fixed. Remove the linker portion to define the fixed R-groups, which must be two separate neutral fragments connected by single bonds.
You can load additional linker structures to supplement the built-in linker library.
Configure LigPrep and Glide Docking settings, or use the defaults. Select the docking input file, reference ligand file, and grid file.
In the Filters tab, configure the Target Property Space, Excluded SMARTS, Maximum linker HAC perturbation, and any additional filters as needed.
Configure job settings. You should use a minimum of 1,024 processors.
Click Run to submit the job, or use the Write option to save job files for manual submission on a cluster.
For best practices on starting ligand selection, LigPrep charge state validation, and docking model setup, see AutoDesigner Best Practices.
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.
AutoDesigner - Linker Design Panel Features
The panel is organized into two tabs: Setup and Filters.
Setup tab
- Starting Ligand text and load button
- Use custom settings option
- Docking input file file path and Browse button
- AutoDesigner Best Practices link
- Define Filters link
Filters tab
- Excluded SMARTS file path and Browse button
- Similarity score option
- Calculate QED score option
- Epik pKa option
- Phase hypothesis option
Setup tab
- Starting Ligand text and load button
Select a single ligand structure as the starting input for the (Undefined variable: Snippet.product_name) algorithm. Import from the Project Table or Workspace and click Load. The starting ligand is neutralized upon loading. Only neutral, single-ligand structures are accepted.
- Additional linkers text and load button
Import additional linker structures from the Project Table or a SMILES file. These linkers are added to the built-in linker library and are subjected to the same transformation and filtering stages as the built-in linkers.
- Common R-groups display area
Displays a 2D representation of the two fixed R-groups defined for the starting ligand. After loading a starting ligand, a copy of the ligand appears here. Remove the linker portion of the molecule in the sketcher to define the two fixed R-groups.
- Edit in 2D sketcher button
Click this button to open the 2D sketcher dialog. Remove the linker portion of the molecule to define the two fixed R-groups. The R-groups must be two separate neutral fragments, each attached via a single bond. In Linker Design, both R-groups are kept constant while the linker connecting them is replaced with novel linkers.
- Use custom settings option
Select this option to enter custom LigPrep settings in the text box. If not selected, the default (Undefined variable: Snippet.product_name) LigPrep settings are used, which generate tautomers and ionization states with Epik, produce up to 32 stereoisomers per input structure, and apply a pH tolerance of 0.5.
- Use custom filter file option
Select this option and click Browse to upload a custom LigPrep property filter file. If not selected, standard (Undefined variable: Snippet.product_name) filter files are generated and used. The default filter removes ligands with an Epik state penalty greater than 1 in intermediary filtering cascades and greater than 0.5 in the final filtering cascade.
- Docking input file file path and Browse button
Click Browse to select a Glide input file (.in). The docking model must include core constraints. The intermediary filtering cascades use only the core constraint, while the final filtering cascade uses all constraints present in the input file, including any hydrogen bond or positional constraints.
- AutoDesigner Best Practices link
Click this link to display the AutoDesigner Best Practices topic, which provides guidance on starting ligand selection, LigPrep charge state validation, and docking model setup.
- Define Filters link
Click this link to switch to the Filters tab. The label changes to Change Filters after any filter settings have been modified.
Filters tab
- Excluded SMARTS file path and Browse button
Click Browse to select an optional SMARTS file (.sma) containing patterns to exclude from the (Undefined variable: Snippet.product_name) output. Each line in the file specifies one SMARTS pattern, and compounds matching any pattern are filtered out. Use this to exclude previously explored series or competitor compounds.
- Target Property Space Select button menu
Click Select to configure or import Target Property Space settings. Choose Configure to open the Target Property Space dialog, where 21 physicochemical properties can be set with minimum and maximum values. The property ranges are automatically populated from the descriptors calculated for the starting ligand, and they update whenever the starting ligand is changed. Choose Import to load previously saved settings from a .propspace file. By default, the property space must include the starting ligand properties. Uncheck Require property space include starting ligand to allow the property space to fall outside the starting ligand values. Settings can be saved using the Export button in the dialog.
The 21 configurable properties include molecular weight, fraction sp3, PSA, AlogP, total rotatable bonds, consecutive rotatable bonds, chiral centers, ring counts (total, aromatic, saturated), spiro atoms, bridgehead atoms, hydrogen bond acceptors, hydrogen bond donors, maximum ring size, sulfur atoms, alkynes, quaternary carbons, 5,5-fused ring systems, ligand total charge, and ligand absolute total charge.
- Maximum linker HAC perturbation text box
Set the maximum number of heavy atoms allowed in the linker. This controls the size of the linker region that connects the two fixed R-groups. The default value is 10, with a range of 1 to 20.
- Similarity score option
Select this option to calculate the Tanimoto similarity of the newly generated linkers with the linkers of up to 5 compounds from the Project Table. Compounds with a maximum Tanimoto similarity below 0.1 are filtered out. The Tanimoto similarity score for each selected reference structure is included in the output properties.
- Calculate QED score option
Select this option to calculate the Quantitative Estimate of Drug-likeness (QED) score for each generated compound. The QED score ranges from 0 to 1, where higher values indicate more favorable drug-like properties. The score is included in the output properties. For more information on QED scores, see Bickerton et al.
- Epik pKa option
Select this option to filter molecules based on the pKa of the linker region explored by the Linker Design job. Molecules are filtered if the pKa of hydrogens on a formally charged nitrogen atom falls outside the specified range. This filter can be used to modulate the pKa of basic amine-containing molecules.
- Phase hypothesis option
Select this option and click Browse to select a Phase hypothesis file (.phypo) generated in Maestro. The final docked poses are scored in place against the pharmacophore hypothesis, and compounds that do not match the required minimum number of phase sites are filtered out. The Phase pharmacophore hypothesis can be set up using the Develop Pharmacophore Model Panel.
- Job toolbar
Manage job submission and settings. See Job Toolbar for a description of this toolbar.
- Status bar
to reset the panel to its default settings and clear any data from the panel.If you can submit a job from the panel, the status bar displays information about the current job settings and status for the panel. The settings include 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.
The status bar also contains the Help button
, which opens an option menu with choices to open the help topic for the panel (Documentation), launch Maestro Assistant, or if available, choose from an option menu of Tutorials. If the panel is used by one or more tutorials, hover over the Tutorials option to display a list of tutorials. Choosing a tutorial opens the tutorial topic.