Spark™

Ligand linking and joining

Identify linkers, from real chemistry, to join two ligands using bioisostere replacement in Spark

Selecting the two ligands to be joined in Spark
Selecting the two ligands to be joined within the Spark protein editor.
The Spark ligand joining wizard interface
Spark wizard-based interface to guide you through the setting of the Spark ligand joining experiment.
Selecting the region of the first ligand to replace/grow from.
Selecting the region of the first ligand to replace/grow from.
Selecting the region of the second ligand to replace/grow from.
Selecting the region of the second ligand to replace/grow from.
Selecting the allowed atom types at the attachment points.
Selecting the allowed atom types at the attachment points.
Selecting which fragment databases will be searched as part of the ligand joining experiment.
Selecting which fragment databases will be searched as part of the ligand joining experiment.

Identify linkers to join your ligands

Many drug targets hold multiple binding areas within their protein active site. In situations where two ligands or fragments have been identified at adjacent binding sites, Spark’s ‘Join Two Ligands’ experiment enables design scientists to find a suitable linker and form a larger molecule that combines the binding interactions of the two starter structures.

  • Upload the two starting ligands, and define the region of each molecule to be replaced by a linker
  • Find suitable fragments, from a large collection of chemical databases, with the right number of connection points and correct geometry to the starter molecules
  • Merge the fragments to form the product structures and score these based on their electrostatic similarity and shape to the starting molecules
Selecting the two ligands to be joined in Spark
Selecting the two ligands to be joined within the Spark protein editor.
The Spark ligand joining wizard interface
Spark wizard-based interface to guide you through the setting of the Spark ligand joining experiment.
Selecting the region of the first ligand to replace/grow from.
Selecting the region of the first ligand to replace/grow from.
Selecting the region of the second ligand to replace/grow from.
Selecting the region of the second ligand to replace/grow from.
Selecting the allowed atom types at the attachment points.
Selecting the allowed atom types at the attachment points.
Selecting which fragment databases will be searched as part of the ligand joining experiment.
Selecting which fragment databases will be searched as part of the ligand joining experiment.
Standard results view for Spark ligand joining experiments
Starter molecules (top left) and results displayed from the Spark ligand joining experiment using the standard ‘Results’ view. This view shows all the suggested replacement fragments, initially sorted by score, and a traffic light scheme for color coding properties.
Clustered results view for the Spark ligand joining experiment
Starter molecules (top left) and results displayed from the Spark ligand joining experiment using the ‘Clustered’ results view. In this view, molecular results are grouped into clusters that represent families of results that broadly belong to the same chemotype.
Tile results view from the Spark ligand joining experiment
Starter molecules (top left) and results displayed from the Spark ligand joining experiment using the ‘Tile’ results view. This view offers a more compact version of the standard results, holding pictorial data, such as the structure or radial plot, plus numerical or string data.

Visually meaningful analysis of results

Once the calculation is complete, the diverse collection of novel results produced by Spark will be displayed. These results show the scored fragments alongside additional information and property-based coloring to facilitate results triaging and prioritization. Spark results can be visualized in three different modes, each offering different views and groupings of molecular data.

Results can also be exported into our CADD platform Flare™ to help you prioritize, via a wide portfolio of ideas and methods, the best molecules to make.

View poster: 'Effective methods for fragment growing, joining, and cyclization'
Standard results view for Spark ligand joining experiments
Starter molecules (top left) and results displayed from the Spark ligand joining experiment using the standard ‘Results’ view. This view shows all the suggested replacement fragments, initially sorted by score, and a traffic light scheme for color coding properties.
Clustered results view for the Spark ligand joining experiment
Starter molecules (top left) and results displayed from the Spark ligand joining experiment using the ‘Clustered’ results view. In this view, molecular results are grouped into clusters that represent families of results that broadly belong to the same chemotype.
Tile results view from the Spark ligand joining experiment
Starter molecules (top left) and results displayed from the Spark ligand joining experiment using the ‘Tile’ results view. This view offers a more compact version of the standard results, holding pictorial data, such as the structure or radial plot, plus numerical or string data.

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