AutoDesigner - Core Design Panel

Set up and run an AutoDesigner workflow to explore core scaffold chemical space with docking-based scoring and filtering.

To display this panel, do one of the following:
  • click the Tasks button and browse to De Novo Design → AutoDesigner Core Design
  • Overview
  • Using
  • Features
  • Additional Resources

Overview

AutoDesigner Core Design (CoreDesign) is a de novo design workflow that explores core scaffold chemical space to generate novel compounds with docking-based scoring and filtering. The workflow keeps a single R-group constant while replacing the original core and additional R-groups with novel scaffolds. The generated compounds can be used as input for Active-Learning FEP+.

CoreDesign is best suited for hit identification and backup series exploration, where the goal is to discover novel scaffolds rather than optimize an existing one. It uses a completely different design algorithm from AutoDesigner R-Group Design: instead of exploring variations at a single R-group position, CoreDesign explores scaffolds and R-groups simultaneously by keeping a single fixed R-group and replacing the entire core and any additional R-groups. CoreDesign requires a high-quality protein structure and a validated FEP+ model. It is target-agnostic and can be applied to any structurally enabled target.

The CoreDesign algorithm uses a multistage search approach:

  1. A combination of an expert-curated built-in Core Library and optional user-provided scaffolds is subjected to over 300 million matched molecular pair transforms and a set of curated transforms.

  2. All generated cores are combined with the initial core library and filtered using a physicochemical property filter to produce the Scaffold Library.

  3. The common R-group is attached at all possible positions of the Scaffold Library.

  4. The output is filtered and decorated up to two more times with the R-group Library.

  5. In the final filter cascade, all ligands are filtered using the Target Property Space, a complexity filter, SMARTS-based substructure filter, FEP+ amenability filter, excluded SMARTS filter, LigPrep filter, Glide docking filter, and any optional additional filters.

CoreDesign uses progressive filtering cascades. Intermediary Filter Cascades use fewer filters and allow compounds through that could potentially be rescued in later stages. The Final Filter Cascade uses all available filters with the strictest settings to retain only compounds meeting all criteria. The filtering cascade includes over 1,500 proprietary SMARTS patterns that capture basic chemistry rules, chemical stability, and medicinal chemistry liabilities. The substructure-based filtering is automatically adjusted each run to ensure the starting ligand and fixed R-group pass the substructure filter.

Using the AutoDesigner - Core Design Panel

To set up a CoreDesign job:

  1. Prepare the Glide input files: a grid file, a docking input file with core constraints, and a reference ligand file. For detailed instructions, see AutoDesigner Core Design Documentation .

  2. In the Setup tab, load a starting ligand and click Edit in Sketcher to define the common R-group. Use the R+ button to place the core attachment point, then click Save.

  3. You can load additional input cores to supplement the built-in Core Library.

  4. Configure LigPrep and Glide Docking settings, or use the defaults. Select the docking input file, reference ligand file, and grid file.

  5. In the Filters tab, configure the Target Property Space, Excluded SMARTS, FEP Amenability Filter, and any additional filters as needed.

  6. Configure job settings. You should use a minimum of 1,024 processors. The driver node should have 8 cores, 64 GB RAM, and 2 TB SSD scratch. Compute nodes should have 16 cores, 32 GB RAM, and 200 GB scratch.

  7. Click Run to submit the job, or use the Write option to save job files for manual submission on a cluster.

The job produces the full set of output structures (coredesign_full.maegz), a randomly selected sample of 1,000 compounds (coredesign.maegz), and a log file (coredesign.log).

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. For information on command usage and options, see coredesign.py Command Help.

AutoDesigner - Core Design Panel Features

The panel is organized into two tabs: Setup and Filters.

Setup tab

Filters tab

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 input cores text and load button

Import additional input core structures from the Project Table or a SMILES file. These cores are added to the built-in Core Library and are subjected to the same transformation and filtering stages as the built-in cores.

Common R-group display area

Displays a 2D representation of the common R-group defined for the starting ligand. After loading a starting ligand, a copy of the ligand appears here. Use Edit in Sketcher to mark the core attachment point and define the R-group to keep constant.

Edit in Sketcher button

Click this button to open the 2D sketcher dialog. Use the R+ button to place an attachment point indicating the location of the core, then click Save. In CoreDesign, the common R-group is kept constant while the original core and additional R-groups are replaced with novel scaffolds. The sketcher only accepts neutral structures.

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.

Reference ligand file file path and Browse button

Click Browse to select a reference ligand file (.reflig.maegz) that defines the reference structure and core constraint for docking. It is recommended to use the fixed common R-group as the reference ligand and the All heavy atoms setting for core atoms to ensure aligned output poses.

Grid file (zip) file path and Browse button

Click Browse to select a Glide grid file (.zip) for the target receptor.

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.

FEP Amenability Filter section

Filters compounds to retain only those suitable for relative binding free energy calculations. A compound is considered amenable if the number of heavy atoms not in the maximum common substructure (MCS) with a reference compound is below the specified threshold for both the compound and the reference. Generally, the starting ligand should be selected as the FEP reference. Selecting more than 1–3 reference ligands is discouraged, as the MCS calculation is performed for every generated molecule against each reference.

FEP References text and load button

Load one or more reference compounds for the FEP+ amenability calculation. Select compounds from the Project Table and click Load, or click Browse to select a SMILES file. The total number of selected reference entries is displayed. A warning appears if any selected entries are not ligands.

FEP Max HAC perturbation text box

Set the maximum number of heavy atoms allowed to change in a perturbation. This is evaluated as the number of heavy atoms in the compound or reference (whichever is greater) minus the number of heavy atoms in the MCS. The default value is 10.

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 new core and R-groups explored by the CoreDesign run. 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.

pKa Min text box

Set the minimum pKa value for the Epik pKa filter. The default value is 6.

pKa Max text box

Set the maximum pKa value for the Epik pKa filter. The default value is 9.

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.

Min phase site to match text box

Set the minimum number of pharmacophore sites that a docked pose must match to pass the Phase hypothesis filter. The default value is 2.

Job toolbar

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

Status bar

Use the Reset button to reset the panel to its default settings and clear any data from the panel. If the panel has a Job toolbar, you can also reset the panel from the Settings button menu.

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.

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