Identify linkers to join your ligands
Powered by Cresset’s field technology, Spark’s ‘product-centric’ approach to bioisosteric replacement enables users to rapidly generate diverse, non-obvious bioisostere ideas in a variety of different experiments.
Many drug targets hold multiple binding areas within their protein active site. Heterobifunctional degraders instead typically consist of a ligand binding to the target protein, a ligand binding to a ligase, and a linker connecting the two ligands. In these cases, Spark’s ‘Join Two Ligands’ experiments enable design scientists to find suitable linkers and form a larger molecule that combines the binding interactions of the two starter ligands or fragments.
Wizards make running Spark experiments simple, by guiding you step-by-step through experiment set-up and execution. In a ligand joining experiment, you select which regions in the two ligands should be joined, and in just a few clicks, Spark finds linkers of suitable length, attachment point geometry, and with the attachment point atom types you have chosen.
The linkers will be taken from your choice of Cresset-generated fragment databases available to all Spark users. Fragments are derived from real molecules from a variety of sources: commercially available compounds and reagents, literature reported compounds, patent data, degrader linkers, agrochemical compounds, small molecule crystal structures, and theoretical ring systems. The new ‘Linkers’ databases are particularly suitable for finding longer linkers, as they include over 9.6K known and commercial targeted protein degradation linkers derived from experimental sources.
You can also create your own linker databases if you wish, using Spark’s database generator.
After the experiment completes, Spark integration within Flare gives access to a wide range of methods for result refinement and post-processing, including Electrostatic Complementarity™, docking, MM/GBSA, Flare FEP.