Cresset KNIME Nodes version 188.8.131.52359 by www.cresset-group.com
Spark™ is a bioisostere replacement tool which suggests biologically relevant replacements (bioisosteres) for key fragments of known active molecules. You load an active molecule into Spark, preferably in the bioactive conformation, select the part of the active that you wish to replace and specify which databases to search. Spark will present a list of biologically relevant replacements ranked using Cresset’s unique molecular field technology (https://www.cresset-group.com/science/), or using Lead Finder™’s docking score (https://www.cresset-group.com/software/lead-finder/). As well as replacing central parts of a molecule, Spark can suggest replacements for terminal groups. It can be used to grow ligands and fragments into unoccupied pockets of the target protein, carry out ligand joining and macrocyclization experiment, and to find a fragment which displaces a crystallographic water molecule near your ligand. Spark comes with a set of databases of fragments generated from whole molecules (e.g. commercially available or literature reported compounds) or from synthetic reagents.
Spark's molecular comparisons using ligand similarity are based on their molecular fields, not on their structure. The interaction between a ligand and a protein involves electrostatic fields and surface properties (e.g. hydrogen bonding, hydrophobic surfaces and so on). Two molecules which both bind to a common active site tend to make similar interactions with the protein and hence have highly similar field properties. Accordingly, using these properties to describe molecules is a powerful tool for the medicinal chemist as it concentrates on the aspects of the molecules that are important for biological activity. Using the fields gives a 'protein's view' of how the molecules would line up in the active site, generating ideas on how molecules with different structures could interact with the same protein. Docking may also be used to score the final result molecules, which can be particularly helpful for guiding ligand growth into unoccupied pockets of the target protein and to find novel results making interactions with the active site of the protein not mapped by an existing starter or reference molecule.
The major advance in Spark compared to previous bioisostere replacement tools is that Spark scores each potential replacement in context. Each candidate fragment is merged into the starting molecule and energy minimized before scoring. With ligand similarity scoring, the full field pattern for that molecule is calculated, and this is then compared to the starting structure. Alternatively, a docking score is calculated.
The filter options allow you to specify constraints on the type and properties of the fragments to try. Each option has three settings. The 'Yes' option specifies that the specified functionality must be present, the 'No' option specifies that it must not be present and the 'Optional' option specifies that it may or may not be present. For example, setting 'Contains an aromatic ring' to 'Yes' means that all suggested replacement fragments must contain an aromatic ring. Setting 'Contains a non-ring atom or bond' to 'No' will specify that only ring fragments with no exocyclic components may be used. The non-obvious flags are explained below under 'Filters'.
Constraints can be set to bias the Spark search and penalize results which do not satisfy the constraint. Three types of constraints are available:
The advanced options allow you to further refine the Spark search.
This node wraps the executable 'sparkcl', which must be installed with a valid license for this node to work. If this is installed in the default location on Windows, then it should be found automatically. Otherwise, you must either set the 'Cresset Home' preference or the CRESSET_HOME environment variable to the base Cresset software install directory. You may also set the 'sparkcl Path' preference or the CRESSET_SPARKCL_EXE environment variable to point directly at the executable itself.
The Spark Database Search node can be configured to use additional resources to perform calculations. The time taken for the node to run will be drastically reduced if you use the Cresset's Engine Broker. To use this facility either set the "Cresset's Engine Broker" preference or the CRESSET_BROKER environment variable to point to the location of your local Engine Broker. If you do not currently have the Cresset Engine Broker then contact Cresset (email@example.com) for pricing on local and cloud based brokers.
If 'Fragment selection input method' is set to 'Specify bonds to break'
The bonds in the starter molecule that are to be broken. Each line should only list one bond to break in the format:
The available attachment point flags are: Br, C, Car, Cl, Csp, Csp2, Csp3, F, Hal, I, N, Nsp2, Nsp3, O, Osp3, P, PS, S.
For example the following will break 2 bonds between atoms 10, 9 and atoms 24, 14. The region of the molecule containing atoms 9 and 14 will be replaced. Atom 9 will only be replaced with a Nsp3 or Nsp2 atom while atom 14 can be replaced with any type of atom.
If 'Fragment selection input method' is set to 'Specify the atoms to replace'
The atom ids for the atoms to be replaced. The format should be a comma separated list of atom ids in the format atom1,atom2,atom3,...
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