Ligand Designer Panel

Ligand Designer Panel Features

• Workspace Analysis
  • Analyze Workspace button
  • Adjust view and style when analyzing option
• Favorites tools
  • Favorites button
  • Favorites menu button
• Ligand review buttons
• Workflows option menu
  • Banners
    • Explore Ligand Side Chain banner
    • Modify lead banner
• Display section
  • Settings button
  • Collapse/expand button
  • Display options
• View similar purchasable compounds link
• Multi-Parameter Optimization section
  • Settings button
  • Collapse/expand button
  • Radar plot of property values
  • Property values
• 2-D Sketch section
  • 2D Sketcher
  • Predict Pose option menu
  • Minimize Ligand button
• Post-Processing section
  • Collapse/expand button
  • Action menu
  • Scope option menu
  • Action button
• Status and progress area
• Reset button

Workspace Analysis

The first view of the panel involves analyzing a ligand-receptor complex that is included in the Workspace, to determine the growth space for additions to the ligand.

Analyze Workspace button

Analyze the receptor and ligand in the Workspace to locate the "growth space"—regions around the ligand that are large enough to add functional groups that could improve the receptor-ligand interactions. The solvent-exposed region of the ligand is also identified. The growth space is displayed by default as part of the setup.

You must have a receptor (or two receptors) and a ligand in the Workspace to perform the analysis. The ligand must be non-covalently bound to the receptor. Alternate positions of any atoms are discarded. You can also have one or more water maps (see WaterMap - Examine Results Panel), to include stable and unstable waters in the analysis and design process—see WaterMap-Guided Lead Optimization with the Ligand Designer for a tutorial example. The structures and water map are copied to a new entry group, named Ligand Designer. The new group is selected, and the entries in the new group are included in the Workspace. The receptor and the water map entries are also fixed in the Workspace (but not the ligand).

If the receptor has multiple ligands, a dialog box opens so that you can choose the ligand you want to work with. If the ligand is in the entry for the complex, the title of the ligand in the new entry group is the residue name and residue number. If two receptors are used, and each receptor has its ligand occupying the same binding site region, there may be clashing atoms between the active ligand and primary receptor. In this case, a dialog box opens so that you can select the primary receptor. In the subsequent Ligand Selection dialog, the Ligand Clashes column will update with each new selection displaying the number of clashes with the currently selected ligand in the dialog. Selecting the checkbox in the Remove column will allow remove the ligand in that row if that ligand belongs to the primary receptor.

By default, the Workspace view and style are set up for the design process. If you want to retain the Workspace structures, style, and view as they are before analysis, clear the Adjust view when analyzing check box.

Adjust view and style when analyzing option

Change the style and positioning of the Workspace features, to hide the receptor and show the ligand, in ball-and-stick representation with green carbons, and fitted to the Workspace. Metal atoms that the ligand interacts directly with are also shown, as spheres, as are structural waters (within 5 Å of the ligand). Dotted lines marking interactions with the receptor are also shown by default (see Interactions Toolbox for more information).

If this option not selected, the structures in the Workspace remain where they are with the same style.

The option setting is stored as a preference and reapplied when you open the panel again (in the current or a new Maestro session).

If you replace the receptor in the Ligand Designer entry group with a different receptor, the panel reverts to this first view and you must analyze the Workspace with the new receptor.

If you have two receptors in the Workspace you are prompted to choose the primary target, called Receptor 1, for which binding is optimized. The other receptor (Receptor 2) is then treated as a secondary target, for example, an off-target receptor for which you want to ensure poor or no ligand binding. The two receptors should have their binding sites aligned as well as possible. When dealing with the two receptors, only the growth space unique to Receptor 1 and common to both receptors is shown. This information may be useful for designing a ligand that binds to Receptor 1 but not to Receptor 2.

Favorites tools

To assist in the choice of suitable structures, you can designate structures as favorites, and collect these structures into a subgroup or limit the review of generated structures to the favorites.

Favorites button

Click this button to mark the Workspace ligand as a favorite if it is not, and to remove it from favorites if it is. Sets or clears the Mark property on the project entry. The star also shows the status of the Workspace ligand: it is filled if the ligand is a favorite, empty if not.

For multiple ligands in the Workspace, where some are not favorites, the star is part filled, and clicking it makes all the ligands favorites. If all ligands in the Workspace are favorites, the star is filled, and clicking it removes them all from favorites. Likewise, if none of them are favorites, the star is empty, and clicking it makes them all favorites.

Favorites menu

Choose an action to perform on the favorites.

• Group favorites in Project—create an entry group in the Maestro project that contains copies of the favorites. The group is added as a subgroup of the Ligand Designer group, named Favorites.
• Include only favorites—Select the favorites in the project, and show only them in the Workspace.
• Review only favorites—when stepping through ligands with the ligand review buttons, only step through the favorites. Selects the favorites in the project and includes the first in the Workspace.
• Review all—reset the action of the ligand review buttons so that they step through all the selected ligands. Selects all enumerated ligands and includes the first in the Workspace.

Ligand review buttons

These arrow buttons allow you to step through the selected set of ligands. You can also use the right and left arrow keys.

Workflows option menu

Choose a workflow to apply to the ligand structure. The action opens a series of banners in the Workspace that lead you through the steps involved in the workflow. Selection of R-group libraries and filtering of enumerated ligands can be done in many of the workflows. Most workflows involve an enumeration step; all of them produce at least one new ligand, if successful.

The new ligands are docked with Glide using MCS constraints to the input ligand, and the docked poses are returned into a new entry group. The group is placed as a subgroup of the parent ligand structure, except for Favorites and for hybridizing ligands, where the group is at the same level as the parent group. The group name includes the ligand name and the name of the workflow, along with any other text needed to make the name unique. The titles of the ligands in the group are composed of the parent ligand title and a serial number, and other text to make the name unique in the Ligand Designer group (not just the subgroup).

• Attach R Group—attach a group at a particular location in the ligand. This workflow performs an R-group enumeration at a bond that you choose, with a small diverse library. It is useful to display Pathfinder bonds for this workflow, so you can enumerate at a location that can be substituted in a known synthetic route.

• Fill Growth Space—Fill a growth space that you select by picking. This workflow performs an R-group enumeration on ligand locations that are adjacent to the growth space you select, with constraints that the R groups are contained in the picked growth space. The resulting ligands are docked to the primary receptor.

  When you are picking the growth space to use, the growth space is outlined in yellow; it includes empty regions within a defined distance of the pointer position. If there are two receptors, the growth space for both receptors is shown: cyan for the primary receptor only, pink for the common growth space, and yellow for the second receptor only. You can only pick a growth space to fill for the primary receptor. Choosing the unique growth space for the primary receptor is likely to increase the selectivity for the primary receptor, whereas choosing the common growth space can improve binding to both receptors.

• Bioisostere Replacement—replace atoms or groups within a set of selected atoms with bioisosteres. Choose all the atoms or groups that you want to target for the search for possible bioisosteres.

• Isostere Scanning—Scan for possible replacement of an atom or group with an isostere (groups like halogens, methyl/methylene, hydroxyl/ether, amine, amide). The results for each isostere type are stored in separate subgroups of the group created for the workflow.

• Displace Unstable Water—Displace an unstable water with an addition to the ligand. If the displaceable waters are hidden, they are shown. First you choose the water to displace, then the ligand side chain site to enumerate, then do the enumeration. This workflow can also be started by clicking on an unstable (displaceable) water in the Workspace, and proceeds with selection of the side chain site.

  Only available if a water map was included in the Workspace for analysis.

• Replace Stable Water— Replace a stable water with an addition to the ligand that can form a hydrogen bond to the receptor. If the replaceable waters are hidden, they are shown. First you choose the water, then the ligand side chain site to enumerate, then do the enumeration. This workflow can also be started by clicking on an unstable (displaceable) water in the Workspace, and proceeds with selection of the side chain site.

  Only available if a water map was included in the Workspace for analysis.

• Form Ligand-Receptor Interaction—Form noncovalent interactions between the receptor and the ligand by adding to the ligand. These interactions can be hydrogen bond, pi-pi or pi-cation interactions, or salt bridges. First you pick an interaction marker, then a ligand side chain, then enumerate. This workflow can also be started by clicking on an interaction marker in the Workspace.

• Ring Swap— Select a ring core in a ligand, then select an option the from ring library to swap the core and produce enumerated ligands. Selecting this option displays a banner instructing you to select a ring system by clicking in the Workspace. Once a ring is selected, the Ring Swap dialog appears, with the gear icon and the Enumerate button. Click the gear icon to open the Ring Swap Settings dialog, where you can click an option from the ring library to swap with the selected ring system. Rings available for selection will be highlighted. Holding the Shift key while clicking additional atoms connected to the selected ring atoms will include the additional atoms in the enlarged ring system. Additionally, clicking on a torus or hydrophobic sphere will select the corresponding ring atoms. Click the Enumerate button to start the process, and a banner appears indicating that the ring swap has started. Once complete, the results will be added to the Project Table.

• Core Swap (Beta)— Select the first bond pointing in the direction to where the core starts, then select the second bond pointing in the direction where the core ends. Additional bonds can be included to define the core. If at least two valid bonds defining the core are selected, the Enumerate button is available to start the process. Click the gear icon to open the Ligand Designer - Core Swap Settings Dialog Box

• Macrocyclization—Form a cyclic ligand from a ligand that forms a loop with a relatively short distance between two points near the ends the loop (a few bond lengths). The connecting fragment, composed of selected spacers, is enumerated for several choices of joining points, chosen automatically. Additionally, you can select limb atoms by selecting Pick custom attachment points in the banner. You can select spacers in the Macrocyclization Settings Dialog Box, which you open by clicking the Settings button in the banner.

• Hybridize Ligands—Swap groups between two or more ligands to create new ligands, using the Breed algorithm (see Breed Panel for more information). The swapping is done by identifying overlapping bonds, i.e. bonds that are in the same location and direction in both ligands in the swap. Ring bonds are excluded from swapping. The ligands must be properly aligned, and included in the Workspace. Only the unique new ligands are returned.

• 2D/3D Editing—Open a 2D Sketcher instance in place of the Multi-Parameter Optimization radar plot, and the 3D Builder panel. You can sketch a ligand in 2D, or edit the structure in the Workspace in 3D, and then predict the pose of the ligand. See Sketcher section and Building and Editing Structures for more information on the editing tools. The 2D structure and the 3D structure are kept in sync. Click Predict Pose in the banner to run the MCS docking of the ligands and return the found poses into a new entry group, 2D/3D Designs - title. To finish editing, close the 2D Sketcher. The original ligand is redisplayed in the Workspace, discarding any edits; only the structures that were docked are kept.

• Dock ligands from file—Dock a set of ligands from a file. The ligand file can contain 3D structures in Maestro or SD format or it can contain SMILES strings (but not both). It should not have a large number of ligands, as the docking is done interactively. Opens a dialog box for selection of the ligand file, then a banner for docking the poses. Click Predict Pose in the banner to run the MCS docking of the ligands and return the found poses into a new entry group, Docked Poses.

Banners

The workflow actions open a series of banners in the Workspace. Many of them involve a simple single action; a few have more possibilities, and are described below.

Explore Ligand Side Chain banner

This banner prompts to choose a ligand side chain (bond) at which the enumeration starts. The available side chains are marked with arrows. Orange arrows indicate sites where regular R-group enumeration is done; purple arrows indicate sites where reaction-based enumeration can be done. Choosing a purple arrow displays the Use reaction-based enumeration option in the Modify lead banner, which is displayed after you have picked the bond.

Modify lead banner

This banner is displayed at the end of several workflows, and has several features to perform actions:

• Enumerate button — Start the enumeration to modify the lead. The banner closes once the enumeration starts, and progress is displayed in the status area of the panel.
• Filter button — Set up property-based or SMARTS-based filters—see below.
• Settings button —Choose libraries for enumeration—see below.
• Use reaction-based enumeration option — Enumerate at the site using reaction-based enumeration (see Reaction-Based Enumeration Panel for more information). This option is available when you select a bond for enumeration that is marked in purple. The purple marker indicates that synthetic routes are known for addition of groups at this location. If this option is selected, the Settings button is hidden. The reaction-based enumeration takes longer than the regular R-group enumeration.

The filter and settings button are colored blue if filters or settings are currently active.

Several of the banners have buttons for filtering the results, controlling picking, or making settings:

• Filter button — Set up property-based or SMARTS-based filters to filter the results of the enumeration. The filters can be different from those set up in the multi-parameter optimization. The button opens a menu from which you can open the Ligand Designer - Filter by Property Value Dialog Box or the Filter by SMARTS Dialog Box.
• Pick option — This option allows you to turn on and off picking for the banner action, so that you can perform some other action that requires picking. You might (for example) need to change the Workspace view while in this mode. Turning off the Pick option turns on normal Workspace picking with the Select (arrow) button in the main window. Likewise, clicking the Select button turns the Pick option in the banner off. You can turn it on again to resume picking.
• Settings button —For enumeration of a single site, you can use this button to choose the libraries used for the enumeration. This is useful if you want to use your own R-group libraries. By default, a built-in library is chosen that is designed for the chosen workflow. The button opens the Ligand Designer - Enumeration Settings Dialog Box. For cyclization, the button opens the Macrocyclization Settings Dialog Box, so you can choose or customize the spacers used to link two sites in the ligand.

These buttons are colored blue when filtering or custom settings are in use.

Display section

This section provides controls for what is shown in the Workspace. You can collapse or expand this section using the button

Settings button

Make settings for the style of the Workspace objects. Opens the Display Settings Dialog Box.

Collapse/expand button

Collapse the Display section so that only the top part with the title and tools is visible. This allows more space for the rest of the panel, when your focus is on a different task. The expand button restores the Display section to its previous size.

Display options

Select the objects you want to display in the Workspace.

• Ligand-Receptor Interactions—Display markers at the location of nearby receptor pharmacophore sites—acceptor, donor, hydrophobic, negative, positive, ring. Acceptors are displayed as hemispheres, donors as cones indicating the favorable hydrogen bonding direction; rings are displayed as orange rings, and the rest as colored spheres. Each marker is annotated with the pharmacophore type and the residue name and number. If the pointer is over one of the markers, it is highlighted, and the residue is displayed in ball-and-stick representation until you move the pointer. Acceptor and donor markers are enlarged to show their range. If there is an existing interaction with the ligand it is indicated with dotted lines. If you click on a marker, the residue is shown and a banner is displayed for enumerating ligand-receptor interactions.

• Ring Systems— Display aromatic and aliphatic rings with phase markers denoted by orange donuts and green spheres, respectively.

• Displaceable Waters—These are unstable waters, usually near a hydrophobic region, that could be displaced by the ligand. They are displayed as colored spheres, with the ΔG (simple) color scheme from WaterMap—brownish for values near zero, redder for more positive values. You can make settings to define these waters and which ones to display in the Display Settings Dialog Box. If you click on a water, a banner is displayed for displacing the water.

  Only available if a water map was included in the Workspace for analysis.

• Replaceable Waters—These are stable waters that could be replaced by the ligand to form hydrogen bonds with the receptor. They are displayed as colored spheres, with the ΔG (simple) color scheme from WaterMap—brownish for values near zero, greener for more negative values. You can make settings to define these waters and which ones to display in the Display Settings Dialog Box. If you click on a water, a banner is displayed for replacing the water.

  Only available if a water map was included in the Workspace for analysis.

• Growth Space—This is the space into which the ligand can be grown, between the ligand and the receptor and out into the solvent. The region can include waters, but might also be empty. The region only includes space that is large enough to fit an extension to the ligand. The region between the ligand and the receptor is represented as a light blue cloud. The solvent-exposed region near the ligand is represented as a dark blue cloud. You can change the colors of these regions in the Display Settings Dialog Box. Spherical regions in the growth space are highlighted in yellow when the pointer is over them. If you click on one of these regions, a banner is displayed for growing a side chain of the ligand into this region.

  For two receptors, the growth space is colored differently: the unique growth space for each receptor has its own color, and the common growth space has its own color.

  In addition to the growth space, atoms on the ligand are marked if there are clashes (contacts) with the receptor backbone: a yellow highlight is added for bad contacts and a red highlight for ugly contacts. See Pi-Pi and Contact Criteria settings for more information on the contact criteria.

  A color legend for these regions is displayed by default in the Workspace, which you can turn off or on in the Display Settings Dialog Box.

• Pathfinder Bonds—display bonds for which there is a known synthetic route for attachment of functional group at this position, as found by Pathfinder (see Reaction-Based Enumeration Panel for more information). These bonds indicate places where a different functional group could potentially be added. These bonds are marked with a pink highlight.

• Ligand Surface—Display the molecular surface of the ligand. The surface is colored by default with the Atom Partial Charge color scheme, which you can change in the Display Settings Dialog Box.

• Receptor Surface—Display the receptor surface within 2.5 Å of the analyzed ligand, colored (by default) with the Atom Partial Charge color scheme ("interaction map"). You can change the distance and the color scheme in the Display Settings Dialog Box.

View similar purchasable compounds link

View compounds that are similar to the ligand and are available for purchase. A fingerprint similarity search of a large database of purchasable compounds is run on a GPU, and the 10 most similar compounds are displayed in the Purchasable Compounds panel, showing the 2D structure, the compound ID, the percentage similarity to the ligand, and the vendor(s) where the compounds can be purchased.

To find the best docked poses of these compounds, you can select compounds and click the Predict Poses button (or right-click and choose Predict Poses). The number of poses selected is shown on the button. If you don't select any compounds, clicking the button predicts poses for all of the compounds. The successfully docked poses are added to the Project Table in a new entry group named Purchasable Compounds under the ligand in the Ligand Designer group. If you want to control the ionization state or the stereochemistry of the compounds when poses are predicted, click the Dock Settings link, and make choices from the option menus. For more information on the choices, see the LigPrep Panel topic.

The database search is run using the default values in the FPsim-GPU Panel, and requires a license for the FPsim-GPU product; a warning is displayed if no license is found. The link is available for the initial compound used for the design, and after an enumeration has finished.

Multi-Parameter Optimization section

In this section, you can examine graphically the values of multiple properties and determine whether they meet defined acceptance criteria. In addition, the values of the properties and a normalized MPO score (in the range 0 – 1) are displayed.

Settings button

Change the settings for the optimization. This includes the choice of properties, the importance of each property in the score, and the acceptable ranges of property values. Opens the Multi-Parameter Optimization (MPO) Scoring Panel.

Collapse/expand button

Collapse the Multi-Parameter Optimization section so that only the top part with the title and tools is visible. This allows more space for the rest of the panel, when your focus is on a different task. The expand button restores the Multi-Parameter Optimization section to its previous size.

Radar plot of property values

This plot shows property values for the properties in the multi-parameter optimization (MPO). Each spoke corresponds to a property, which is labeled with the property name. The outermost polygon represents the maximum commonly observed value of the property; the innermost represents the minimum. The dark green shaded area represents the acceptable values of the property. The values of the properties for a given ligand are drawn as an irregular polygon, with lines connecting the property value on each axis. Thus, if the polygon for a ligand lies within the shaded area, it meets the criteria; if any vertex is outside the shaded area, it does not satisfy the criteria.

Property values

Values of the individual properties and the MPO score are given below the radar plot. The values are updated as you change settings in the Multi-Parameter Optimization (MPO) Scoring Panel, and as you sketch ligands in the 2D sketcher. Values in the "good" range (score of 0.8 or higher) are highlighted with a green background, values in the "bad" range (score of 0.2 or lower) are highlighted with a red background.

Sketcher section

This section shows an instance of the 2D sketcher, which you can use to modify ligands.

2D Sketcher

Displays a 2D sketcher with the current ligand imported. You can edit the ligand in 2D. See 2D Sketcher Panel for information on using the tools. The ligand is updated from the Workspace if a new ligand is included or the ligand is modified.

Predict Pose option menu

Predict the pose of the ligand by MCS docking with Glide (the default) or by minimizing the ligand energy. You can choose from these methods by clicking the arrow to the right of this button and selecting one of the items from the menu: MCS docking or Minimization, respectively. The button label changes according to the choice. When predicting a pose, the new pose is added to the Ligand Designer group as a new entry, but is not included in the Workspace. When minimization is done, the new ligand entry is included in the Workspace first and then it is minimized.

The third option in the menu, Docking Ionization, is only enabled when MCS docking is also enabled. Docking Ionization itself has three options: Generate all possible states, Do not change, and Neutralize. If an option other than Do not change is selected, a LigPrep job is first run, then followed by docking.

Post-Processing section

Choose actions to perform on a ligand set after they have been generated or processed through whatever workflows you choose. The ligand set is the ligands in the Ligand Designer group in the project.

Collapse/expand button

Collapse the Post-Processing section so that only the top part with the title and tools is visible. This allows more space for the rest of the panel, when your focus is on a different task. The expand button restores the Post-Processing section to its previous size.

Action menu

Choose the action to apply to the ligands.

• Sort by MPO—Sort the ligands by the values of the MPO score, from best to worst.
• Sort by Clashes—Sort the ligands by the number of clashes between the receptor and ligand, with fewest first. The number of clashes is stored as an entry property (clash count).
• Sort by Good Interactions—Sort the ligands by the number of good interactions between the receptor and ligand, with most first. Good interactions are non-covalent interactions (H-bond, halogen bonds, salt bridges, aromatic H-bonds) and pi-interaction (pi-pi stacking and pi-cation) between the receptor and ligand. The number of good interactions is stored as an entry property (good interactions).
• Load into FEP+—Open the FEP+ Panel with the receptor and ligands loaded. This panel allows you to calculate relative binding free energy values for the ligands.
• Export to LiveDesign—Export the ligands to a LiveDesign instance. Opens the Maestro to LiveDesign Export Panel.
• Save to File—Save the ligand structures to a Maestro or SD file. Opens a file selector, where you can navigate to a location and name the file.
• Export to Spreadsheet—Export properties to a spreadsheet for the selected ligands. Opens the Export Spreadsheet Panel, where you can choose the entries and properties to export, navigate to a location and name the file.

Scope option menu

Choose the set of ligands to apply the action to, from All, Favorites, or Selected.

Action button

Click this button to perform the action. The button is labeled Sort, Save, Load or Export, to match the chosen action.

Status and progress area

Status of a process and a progress bar are displayed below the Post-Processing section. Click the Stop button to stop the current action.

Reset button

Reset the panel to its default settings, clearing all data. In addition, fixed entries are unfixed, and display markers are removed from the Workspace. The panel returns to the Workspace Analysis view. This allows you (for example) to select a ligand that you have designed to optimize interactions with the receptor in one region, and reanalyze the Workspace with this ligand so you can optimize another region.

Related Topics

• Multi-Parameter Optimization (MPO) Scoring Panel
• Display Settings Dialog Box
• Macrocyclization Settings Dialog Box
• Ligand Designer - Enumeration Settings Dialog Box
• Ligand Designer - Filter by Property Value Dialog Box
• WaterMap - Perform Calculation Panel
• WaterMap - Examine Results Panel
• Forming Protein-Ligand Interactions with the Ligand Designer
• WaterMap-Guided Lead Optimization with the Ligand Designer
• Ligand Designer - Core Swap Settings Dialog Box