Displacing crystallographic water molecules with Spark
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.
Water molecules situated within the protein active site can either mediate or impair the interaction between a ligand and a protein. In situations where water stability analysis detects an unstable water molecule, Spark enables users to grow a ligand into the space occupied by that water molecule, displacing it and enabling a more favorable protein-ligand interaction, using a simple workflow.
Wizards make running Spark experiments simple, by guiding you step-by-step through experiment set-up and execution. In a water replacement experiment, you select the portion of your molecule you want to replace, the water molecule to displace, and in just a few clicks, Spark generates a list of replacements displacing the water molecule and mimicking the interactions it makes with the active site of the protein.
Replacement fragments 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.