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Structure-Based Modeling Perspective

The Structure-Based Modeling Perspective offers a user interface ready to explore PDB complexes and to derive pharmacophores from the binding sites. This perspective is divided into two views: the PDB View and the Bookmark View .

PDB View

Besides loading data from file , a very convenient way to obtain ligand-macromolecule complexes is to directly retrieving PDB complexes online . This task can be performed by using the dedicated control panel, the PDB Panel .
Another important use covered by the Structure-Based Modeling Perspective is investigating small-molecule libraries. This can be done either with or without a particular binding site as context by using the Library View .
The PDB View of the Structure-Based Modeling Perspective (1): PDB Panel (2), Zoom Out Widget (3) and Bookmark View button (4)
Figure 4.9. The PDB View of the Structure-Based Modeling Perspective (1): PDB Panel (2), Zoom Out Widget (3) and Bookmark View button (4)

PDB Panel

The PDB Panel displays important information on the current macromolecule-ligand complex, provides instant PDB access and is composed of three components:
  • PDB 4-letter Code Instant Access Box
  • Essential characteristics of the PDB file
  • Ligand Selector
PDB panel
Figure 4.10. PDB panel

LigandScout uses a "two-level" file storing strategy, the Local and Shared Repository . If a PDB code is entered in the PDB 4-letter code field of the PDB Panel, LigandScout tries to find the associated files in the Local Repository, the first stage. If unsuccessful, LigandScout will check the Shared Repository which represents the second level.
Title, class, source, resolution, deposition date, and the experimental type of the current PDB complex are provided in a separate text box.
The Ligand Active Site Selector allows instant access to the active sites of the current complex. Simply click the drop-down menu and select a ligand to zoom into the respective active site. If you are already in an Active Site View the view will be switched without an animation.

3D View Depiction Modes and the Zoom Out Widget

LigandScout's 3D View provides two distinctive macromolecule-ligand complex depiction modes in the Structure-Based Modeling Perspective. Startup sets the display to Macromolecule View . LigandScout memorizes views and positions. Thus, if you change from Active Site View to Macromolecule View using the Zoom Out Widget you will get your previous view setup of the current display. The visibility of the Zoom Out Widget can be toggled in the menu Window > 3D Widgets .
Zoom Out Widget
Figure 4.11. Zoom Out Widget

The Macromolecule View illustrates the global structure and current orientation of the macromolecule. You can switch to the active site by a LEFT mouse click on the active site (blue box). To change back to the Macromolecule View just click on Zoom out button of the Zoom Widget . The Zoom Widget can be placed individually within the 3D View .

Macromolecule View

The Macromolecule View provides structural information on the macromolecule and the ligand's position within it. This view gives you a clearly arranged overview on the current PDB complex. Alpha-helices are shown in dark blue, beta-sheets in light blue, and double helices in brownish-orange. Consecutive amino acids which could not be categorized are shown in gray. If some amino acids or nucleic acids are missing, a gray dashed line will be shown.
Macromolecule View
Figure 4.12. Macromolecule View

Use your mouse to navigate within the 3D View . A single click on Center Ligand and Environment in the toolbar lets you return instantly to the Macromolecule View starting position.
In Macromolecule View , four different rendering modes of both macromolecule and ligand are available. Use the Ligand Default Style submenu of the Render Control menu or the Change Render Style of Selected Atoms icon to change between Line , Ball and Stick , Stick and Spacefilling/CPK ligand rendering mode. Similarly the rendering mode of the macromolecule is changed with the Protein Backbone Default Style submenu of the Render Control menu or the Toggle Hydrogen button. LigandScout supports Lines , Splines , Snake and Ribbon styles.

Active Site View

The Active Site View displays structural information of the ligand and its essential surrounding macromolecular environment in detail. LigandScout displays only amino acids or nucleic acids surrounding the ligand while suppressing moieties irrelevant for macromolecule-ligand interaction. The respective cutoff value is defined in the Preferences/Structure-Based Modeling Settings as Interaction Cutoff Threshold .
Active Site View
Figure 4.13. Active Site View

You can easily switch from Macromolecule View to Active Site View by selecting a ligand in the Ligand Active Site Selector ( PDB Panel ) or by selecting a yellow cube surrounding the ligand in the 3D View . Use the Center Ligand Molecule icon in the toolbar to recenter the ligand. Center Ligand and Environment button lets you recenter the current active site. A click on the Zoom out button of the Zoom Out Widget in the 3D View lets you return to the starting position in the Macromolecule View .
Rendering Options of the Active Site View
The Active Site View provides additional rendering options as available in Macromolecule View . The additional render options are found in the Render Control menu .
Ligand Rendering Settings: Ligand Default Style Submenu
Toggle on/off hydrogen depiction with the Show/Don't Show Hydrogens radio buttons or the Toggle Hydrogen icon. Show Hydrogens Stubs reduces the size of hydrogens to stubs. Show Templates activates the depiction of default geometric templates depending on the hybdridization-state of the currently selected atom. Show Interactions displays all possible interactions of the currently selected atom. Show Ionic Interactions displays ionic interactions between metals and non-metals. The Pickable check box sets the ligand selectable/unselectable.
Environment Rendering Settings: Environment Default Style Submenu
The Environment rendering submenu corresponds in large part to the respective ligand menu and lets you select different rendering modes and define hydrogen handling. The Show Templates option activates the depiction of default geometric templates depending on the hybdridization-state of the currently selected atom. The Pickable check box sets all of the atoms in the environment as selectable/unselectable.
Selection Rendering Settings: Selection Submenu
The Selection submenu lets you customize the rendering of the current selection. LigandScout provides four different modes: Line , Ball and Stick , Stick and Spacefilling/CPK .
Pharmacophore Rendering Settings: Pharmacophore Submenu
The Pharmacophore submenu enables you to switch on/off pharmacophore and excluded volume depiction or use the Toggle Exclusion Volume Spheres Visibility icon. The Pickable check box sets the pharmacophore selectable/unselectable.

GRID Maps Visualization

The Structure-Based Modeling Perspective of LigandScout allows you to visualize GRID maps directly in the protein binding site. To import GRID maps into the binding site, select in the menu File > Open . LigandScout will ask you for the kind of GRID probe to be visualized.
The GRID maps are especially useful for the investigation of LigandScout pharmacophores. These maps provide information on the importance and intensity of certain protein-ligand interactions and may help you to discriminate between crucial pharmacophore features and constraints that are less important. Pharmacophoric features located in areas that indicate strong molecular interactions by GRID analysis (using compatible probes of course) are likely to be highly relevant for the binding of the ligand to the protein.
Since GRID maps do contain absolute coordinates, you need to load the appropriate binding site in order to have the GRID map correctly aligned with the pocket. At best, load the particular binding the GRID map has been calculated for.

Bookmark View

The Bookmark View stores active sites of macromolecules. This has the advantage that you can analyze the binding sites of interest one after the other without the need of loading them through the PDB Panel. The active sites are managed in the Bookmarks Panel.
The Bookmark View of the Structure-Based Modeling Perspective: Bookmarks Panel (1) and PDB View button (2)
Figure 4.14. The Bookmark View of the Structure-Based Modeling Perspective: Bookmarks Panel (1) and PDB View button (2)

Bookmarks Panel

Bookmarks
Figure 4.15. Bookmarks

The Bookmarks Panel allows you to access your bookmarked active sites which are represented by the Bookmark icon. Bookmarks of the current Active Site View are stored using the Copy current binding site to icon located on Copyboard Widget of the the Structure-Based Modeling Perspective. For instance, load 1ke6 into the Structure-Based Modeling Perspective and zoom in. Add the active site to the Bookmark View by the Copy current binding site to . Repeat this procedure for 1ke7 and 1ke8. To access a bookmarked active site simply click on its name in the Bookmark List and the appropriate active site is shown in 3D View. You can erase a certain bookmark entry by selecting it and press the Delete Bookmark button.

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Page designed & authored by G. Wolber

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