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Cresset KNIME Nodes version 2.1.0.20539 by www.cresset-group.com

FieldTemplater is a tool for comparing molecules using their electrostatic and hydrophobic fields in order to find common patterns. When applied to several structurally-distinct molecules with a common activity, FieldTemplater can determine the bioactive conformations and relative alignments of these molecules without requiring any protein information. Other pharmacophore generation packages simply attempt to generate a very crude idea of what the protein wants in terms of donor points, acceptor points and the like: FieldTemplater attempts to provide a full picture of how the active molecules bind, which features they use, what shape they are, and how different series can be compared.

The output of FieldTemplater is a set of 'templates': each template is a model of how the input molecules might align relative to each other in a protein active site.

FieldTemplater utilises Cresset's "field point" technology. Fields are a way of representing molecules in terms of their surface and electrostatic properties: positive and negative electrostatic fields, van der Waals effects and hydrophobic effects on and near the surface of a molecule. Field points are placed at regions where the field has a local maximum. They summarise the most important binding regions of a molecule and can be used both to visually compare fields of two molecules and to accurately determine the overall similarity of the fields of two different molecules.

This node wraps the Field Templater executable 'ftemplater', which must be installed with a valid license for 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 setting or the CRESSET_HOME environment variable to the base Cresset software install directory. You may also set the "ftemplater Path" preference setting or the CRESSET_FIELDTEMPLATER_EXE environment variable to point directly at the executable itself.

The FieldTemplater node can be configured to use additional resources to perform calculations. The time taken for the node to run will be drastically reduced using the Cresset's Engine Broker. To use this facility either set the "Cresset 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 (enquiries@cresset-group.com) for pricing on local and cloud based brokers.

For more information visit www.cresset-group.com or contact us at support@cresset-group.com.

Options

Basic

Column containing input molecules
The column in the first input datatable containing 2-10 input molecules.
Speed
Speed of operation of FieldTemplater. Choose from (in order of decreasing speed, but increasing thoroughness): Quick, Normal or Normal (large mols). Note that changing this option will alter the values of several other options.
Assign formal charges to input molecules
If checked, protonation states for the input molecules are set using Cresset's charging rules. Acids will be deprotonated, primary amines protonated, etc.

Conformer Hunt

Generate at most this number of conformations
The maximum number of conformations to produce per moving molecule. Larger values take longer but give better alignments.
No. of high-T dynamics runs for flexible rings
Most small rings are handled using a ring conformation library. Conformations for rings that are not found in the library are sampled using high-temperature (~600K) dynamics with energy initially distributed into torsional degrees of freedom. The number of dynamics runs (and hence the degree of ring conformation sampling) is set by this value. Values of 2-10 are recommended. Values above 5 make little difference to flexible rings of fewer than 8 atoms.
Gradient cut-off for conformer minimization
All conformers found are minimized using the XED force field. This option sets the gradient cut-off at which the minimization is terminated. Values that are too small lead to insufficient sampling of conformational space and long run times. Values that are too large can lead to unrealistic structures being generated. Values of 0.25 kcal/mol/A to 1.0 kcal/mol/A are recommended with values at the smaller end of the range being preferred if the 'Include coulombics' option is not checked.
Energy window
Conformations that have a minimized energy that is outside the energy window are discarded. The window is calculated from the lowest energy conformation that has been found. The ideal value for this option depends on the 'gradient cut-off for conformer minimization' and 'Include coulombics' options. The best results when the 'Include coulombics' option is not checked are obtained by minimizing to a low gradient (0.1 or better) and applying a smaller energy window (3 kcal/mol) but this significantly increases the time for the calculation. Checking the 'Include coulombics' option requires a significantly larger energy window for large molecules (12 kcal/mol) as these can form very low energy collapsed and internally H-bonded structures.
RMS filter for conformation generation
Sets the similarity threshold below which two conformers are deemed identical. This effectively controls the coarseness of the sampling of conformational space. A low value leads to conformations that are only marginally different, while using a large value means that a conformation near the 'correct' one may not be generated. Values of 0.5 A to 1.0 A are recommended: values at the higher end of the range are more appropriate for larger, more flexible molecules.
Acyclic secondary amides handling
Specify how the conformation hunter is to handle amides.
  • Force amides trans - forces all secondary amides to adopt the trans geometry.
  • Use input amide geometry - leaves secondary amides in the geometry that they were in in the input file, and sets them as non-rotatable. As a result, if the input molecule was drawn with a cis amide then only conformations with cis amides will be generated.
  • Allow amides to spin - allows the amide bind to spin, so a mixture of cis and trans amides can be generated.
Include coulombics
If checked, then the conformer generation process uses the full force field, including long-range electrostatics. Better conformer populations are usually generated with this turned off.

Alignment

Shape weight
The relative weight assigned to shape (as opposed to field) similarity. Values must be between 0.0 (all field) and 1.0 (all shape).
Conformers of achiral molecules can be inverted
Allows conformers of achiral molecules to be inverted if that gives a better alignment. Chiral molecules are never inverted. This must be checked if the imported conformations were exported from Forge or Torch, as the conformer population filters out mirror image conformations.
Atom constraints
Consists of m1,a1,m2,a2,d1[,d2][,s] where
  • m1 = index of molecule 1
  • a1 = index of the atom in molecule 1
  • m2 = index of molecule 2
  • a2 = index of the atom in molecule 2
  • d1 = minimum distance between the atoms in Angstroms
  • d2 = maximum distance between the atoms in Angstroms, same as d1 if not specified
  • s = the constraint strength in A^-2
e.g. 1,1,2,5,2.0 means a constrains atom 1 on molecule 1 and atom 5 on molecule 2 to be 2.0A away from each other, constraint strength 10 A^-2. You may have more than one field constraint specified, separated by newlines. See the Forge manual for a detailed explanation of atom constraints.

Templating

Minimum molecules per Template
The minimum number of molecules which are needed to form a template. With 5 molecules, set this to 5 to only find templates containing 5 molecules.
Maximum molecules per Template
The maximum number of molecules in a template. With 5 molecules, set this to 4 to only find templates with 4 or fewer molecules present. To find all templates with 3 to 5 molecules present, set minimum molecules per template to 3 and maximum molecules per template to 5.
Generate at most this number of pairwise alignments
The maximum number of comparisons (pairwise alignments) used for each pair of molecules. The higher this value, the more templates you will find but the lower quality they will be. This setting is cumulative with the 'Maximum score delta per pair' limit in that the more restrictive setting will be applied for any pair of molecules.
Maximum score delta per pair
Set the maximum difference in score between the best alignment of any given pair of molecules and the worst alignment used in the templating step. For example, with the default value of 0.1, if the best-scoring alignment of molecules A and B has a score of 0.7, then no alignment of A and B with a score less than 0.6 will be used to generate the templates. Again, higher values give more templates. A range of 0.05 to 0.2 is recommended. This setting is cumulative with the 'Generate at most this number of pairwise alignments' setting as the more restrictive will be applied for any pair of molecules.
Minimum link density in a template
The minimum fraction of possible pairwise links that must be used in constructing this template. For example, in a 5 molecule template there are 10 pairs of molecules. A template constructed using 8 pairwise alignments (so that 2 pairs were 'missing') has a density of 0.8, so would not be allowed if this parameter was greater than 0.8. Lower values are recommended for larger sets of molecules (5 or more) where no templates are found. However, please note that templates with a low link density are less reliable.
Filter duplicate templates at RMS
If two templates containing the same conformers of the same molecules are found, then remove the lower-scoring one if they are closer than this limit.

Advanced

Add calculation logs as columns
If checked, the log of the conformer generation and alignment process for each molecule is added as columns 'Molecule_Log_cresset' and 'Template_Log_cresset'.

Input Ports

Two to ten input molecules to be used to generate the templates. The best results are obtained when three to six structurally diverse active molecules are provided.

Output Ports

The templates ordered by descending number of molecules included in each template, then by score (so all 5-molecule templates are listed first, then all 4-molecules ones, etc). Each record in the output table is for one molecule in a template. The "Template" column shows which template the molecule belongs to.
FieldTemplater results stored in a Forge project file. The "Forge Project Viewer" node may be used to view the templates using the FieldTemplater user interface.

Workflows

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