Grow ligands into new spaces in the binding site of your protein
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.
With Spark’s ‘Ligand Growing’ experiments you can grow your molecule or fragment to pick additional interactions with the active site of your protein and increase its binding affinity, guided by existing ligands or fragments mapping a different region of the same active site. When no ligand is available to guide the process, you can grow your ligands into unoccupied parts of the protein active site using the Spark ‘Docking’ method.
Wizards make running Spark experiments simple, by guiding you step-by-step through experiment set-up and execution. In a ligand growing experiment guided by existing ligands, you select the region you want your molecule to grow from, and specify one or more ligands/fragments to guide growth. With just a few clicks Spark generates a list of new possible molecules with similar electrostatic and shape properties to both the original molecule, and the ligands you used to guide growth.
In a Spark ‘Docking’ experiment, you select the region you want your molecule to grow from, define the protein region you want to grow into, and start the experiment with the ‘Docking’ method. This will find new suitable fragments, place them in a sensible orientation within the active site (guided by Cresset’s XED force field), then calculate a docking score for each binding pose to prioritize the best results.
In both types of experiments, the fragments used to grow your molecules 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. You can also create your own fragment 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.