View Hypothesis Workbench

Select a command:

Exclude/OR Edit...

Reset Hydrogen Count

Set Feature Name...

Set Feature Weight...

Estimate Activity...

Compare/Fit...

Merge Hypotheses/Features...

Cluster Hypotheses...

Show Function Mapping...

Add to Dictionary...

Delete from Dictionary...

Show Conformational Model...

Generate Conformational Model

The section below summarizes the use of the Exclude/OR QuickTool. For a more detailed discussion, please refer to the section "The Exclude/OR QuickTool."

To use the Exclude/OR Edit command:

1. In the View Hypothesis workbench, select a feature (fragment or function) to be edited.

2. Select the Exclude/OR Edit command from the Tools menu.

   The Exclude/OR QuickTool opens, displaying two columns containing two windows each. The editor can have any number of columns, with any number of windows in each column. However, only two columns, with two windows per column, are displayed at any time.

   You can use the scroll bars to scroll across the columns, or to scroll up and down through a column.

   The top window in each column is used to represent an alternative allowable feature (an OR in logical terminology), and the windows underneath are used to represent exclusions to the alternative feature in the window at the top of each column.

3. To place an alternative feature in the top window of a column, either select a fragment or function from the Feature Dictionary and then click in the window, or drag and drop a molecule or hypothesis into the window.

   All molecules dropped into the Exclude/OR QuickTool are automatically converted to hypotheses.

4. To add another column to specify another alternative, select the Append OR Column command of the Edit menu in the Exclude/OR QuickTool.

5. To specify an exclusion to an alternative feature, either select a fragment or function from the Feature Dictionary and then click in the window below the appropriate feature, or drag and drop an object from any shelf into the window.

6. To add another exclusion window for a feature, ensure that a window in the desired column is selected, then select the Append Excluding Entry command of the Edit menu in the Exclude/OR QuickTool.

7. To summarize a collection of allowable feature specifications (set associations between corresponding features of alternatives), select the Set Associations command of the Edit menu in the Exclude/OR QuickTool. For more information on using associations, see "Associations".

A molecule that is converted to a hypothesis will have hydrogen counts on all atoms defined as they were in the molecule, thereby eliminating matches with similar compounds that have different hydrogen counts on the matching atoms. To reset the hydrogen count property of any or all atoms to match any value, first select the atoms to be reset using extend selection (middle mouse button). Then select Reset Hydrogen Count.

To set the hydrogen count on an atom in a hypothesis to be a different specific value, use the Set Atom Specification tool in the Toolbox.

1. Select the atom, feature, or node to be named.

2. Select the Set Feature Name command.
   A Rename Feature dialog box is displayed with the default feature name.

3. Change the default feature name in the text box to the new feature name.

4. Select the OK button. The feature name is changed and the box dismissed.

5. To check that the name is set correctly, select the Set Feature Name command and look at the Feature Name dialog box, or take the hypothesis into the Exclude/OR editor.

Features in manually constructed hypotheses in the View Hypothesis workbench have weights that are zero by default. When the weight of one feature is set, the weights of the other features in the hypothesis are set to 1.0 automatically. The hypothesis now can be used in Fit, Score, Estimate and Regress commands. If you set the weight of one feature to be twice the value of another feature, the feature with the higher weight will contribute twice as much to an estimate of activity or to a Fit value. To set all feature weights in a hypothesis to zero, set one of its weights to a value less than or equal to zero; the hypothesis now cannot be used in Fit operations.

Feature weights are computed automatically during the process of generating a hypotheses in the Generate Hypothesis workbench. At present the weights of all features of a generated hypothesis are the same, but different hypotheses have different common feature weights.

To set or modify the weight of a feature:

1. Select the feature, or one of its location constraints, if it has one.

2. From the Tools menu, select the Set Feature Weight command.

3. The Feature Weight dialog box is displayed.

   If a weight has previously been set, the value is displayed in the Weight text box. Otherwise it has a default value of zero.

4. To change the weight, delete the old value and type the new value in the Weight text box.

5. Select the OK button to apply the weight.

   Select the Cancel button to dismiss the dialog without applying the new value.

6. To view the weight of a feature, select the feature and then select the Set Feature Weight command.

   The weight of the feature is displayed in the Weight text box.

Estimate Activity

A compound must have a conformational model before estimating its activity. For details on generating conformers, see "How to Generate Conformers."

A hypothesis used to estimate activity must have an associated regression relationship to account for structure-based activity, which includes having weights assigned to its features. A hypothesis can estimate activity if it has been automatically generated in the Generate Hypothesis workbench or if it has been manually constructed and then had a Regress Hypothesis command performed with a training set of compounds. For more information, see the Regress Hypothesis command. The activity is estimated based upon a regression equation of the form

Estimated Activity = 10 (Intercept - Fit)

as represented in the diagram below. The intercept defines the estimated activity for a Fit of 0.0.

A hypothesis used to estimate activity can have any number of features or location constraints. However, hypotheses are automatically generated with a maximum of five features. Additional features, location constraints, and any excluded volumes must be added manually to the hypothesis in the View Hypothesis workbench. Excluded volumes can be added manually, and are considered in a Fit or Estimate operation to the extent that if any topology in a conformer penetrates the excluded volume sphere in the hypothesis, that mapping is discarded.

To use the Estimate Activity command:

1. On the shelf select the compound to have its activity estimated and the related hypothesis to be used to make the estimate.

2. Select Estimate Activity.

   A Compare/Fit is executed on the selected compound with default settings (Find Best Conformer, Fast Fit, and an Energy Limit set to the energy threshold of the conformational model). After completion of the analysis, the workspace displays the optimally fit conformer mapped to the hypothesis. For a detailed description of fitting a hypothesis to a compound, see "Comparing a Compound to a Hypothesis."

   The Compare/Fit dialog remains displayed to evaluate the results. The Fit readout box reports the Fit value of the compound to the hypothesis. The Fit value indicates how well the conformer fits the hypothesis, taking into account the number of functions which were mapped, and their weights. The Estimate readout box reports the estimated activity of the molecule, based upon its structural similarity with the hypothesis.

   The History Window reports a summary of the hypothesis' characteristics, including the location, weight, and tolerance of each function, and the displacement of each mapped function from the matching compound atom. At the end of the History Window report is the overall Fit value for the optimal conformer, and the maximum possible Fit value for the hypothesis.

See "What does the Compare/Fit command do?" for more details about the process.

• two compounds - performs an RMS geometric comparison of selected atoms in the two compounds, including Fast Fit or Best Fit on the conformers of one or both compounds

• a compound and a hypothesis - for a hypothesis with feature weights, checks that geometric constraints are met and then performs a weighted geometric fit of matching features. For a hypothesis without feature weights, Compare/Fit performs an RMS geometric comparison of selected features in the two objects

• two hypotheses - performs an RMS geometric comparison of matching features

  For an introduction to Compare/Fit, see "What does the Compare/Fit command do?"

For more detailed information, please see Merge Hypotheses/Features Command.

For more detailed information, please see Cluster Hypotheses Command.

To use this command:

1. Display a molecule in the 3D workspace of the View Hypothesis workbench.

2. Select a function in the Feature Dictionary.

3. From the Style menu select the Wireframe command so that you can see all functions clearly (in other styles atoms cover the mapping markers).

4. If there is more than one object in the workspace, left-click on any component in the template molecule to select it.

5. From the Tools menu, select Show Function Mapping.

   If the molecule does not contain any instances of that function, the message "No Mapping" appears in the Status Area above the toolbox.

   If the molecule contains any instances of the selected function, three things are displayed:

   • The Status Area displays the message "Mapping 1/n", where 1 indicates the first instance of the function and n is the number of instances of the selected function that the molecule contains.

   • A colored mapping marker sphere appears, indicating the currently mapped position of the function in the molecule. For a vector function such as HB DONOR or HB ACCEPTOR, you also will see a blue arrow indicating the direction of the hydrogen bond.

   • A dialog box appears in the lower right corner of the workspace. The title of the dialog box indicates the type of the selected function.

     

   To see the next instance of the selected function, select the right arrow in the dialog box. The colored sphere, and any associated vector, moves to the next instance of the selected function. When you are viewing the last instance in the group (n of n), the right arrow button is darkened and does nothing if selected.

6. To scroll back through previous positions of the function in the molecule, select the left arrow button in the dialog box. When you are viewing the first instance again, selecting the left arrow does nothing.

7. To place a function at the position of the displayed sphere in the template molecule, select the Add Function button in the dialog box.

   This command places a function at the location of the currently mapped position in the molecule. The sphere displayed is now an unattached hypothesis function and not a mapping indicator.

8. You can then select a different function from the Feature Dictionary and display instances of this function in the molecule by selecting Show Function Mapping. Use Add Function when the mapping indicator displays a function at a location that you want to include in your hypothesis.

   Note: If more than one function is going to be placed using the template, do not move or rotate anything in the workspace until all functions are added and they are merged with the Merge tool in the Toolbox.

9. To remove the dialog box, select the Cancel button. Note that this does not cancel any added functions; it merely removes the dialog box and the mapping marker from the screen without applying anything.

   You can tie all of the functions together with the Merge Functions tool in the Toolbox, and then attach location constraints with the Define Constraint command from the Constraints menu.

For more information on positioning functions, see "Using a Template Molecule to Place Functions in a Hypothesis."

For information about adding location constraints to features, see "To Add Location Constraints."

1. As a starting point you can drag and drop a hypothesis or molecule from another workbench, build a molecule in the View Compound QuickTool, or you can build a feature/hypothesis in the View Hypothesis workbench.

2. Make any desired modifications to the feature.

   For example, you can take an existing feature, fragment, or hypothesis and generalize (add alternatives) or narrow the specification (define exclusions to the alternatives) in the Exclude/OR editor. Then you can add or merge new functions, reset the hydrogen counts, or modify atom and bond specifications.

   Suppose you convert the molecule CH3OCH(OH)OCH3 to a hypothesis. In order for this substructure feature to be able to bond to other atoms from either terminal carbon, you must reset their hydrogen counts. However, in order to bond through the central carbon (i.e., a terminating substructure), you must reset the hydrogen count of the central carbon.

3. When the new feature has been modified appropriately, select all unconnected features and then select the Merge Features button in the Toolbox.

4. Select Add to Dictionary from the Tools menu.

   The Register Dictionary Feature dialog box appears. It has a 3D workspace that shows the selected feature.

5. In the Name field, enter the name the feature will have in the Dictionary.

6. Select the Function or Fragment button, depending on whether the feature is to be defined and listed as a function or fragment in the Dictionary. (Functions can be mapped with the Show Function Mapping command and can be used in hypothesis generation.)

7. Select OK to add the feature to the Dictionary.

   The dialog box disappears, and the feature is added to the Dictionary.

8. Check that your new feature appears in the Feature Dictionary.

9. Save your StockroomDB before exiting in order to preserve the changes to the Feature Dictionary.

Delete from Dictionary

To delete a feature from the dictionary:

1. In the View Hypothesis workbench, select the Delete from Dictionary command in the Tools menu.

   The Delete Dictionary Feature dialog box appears. It has a 3D workspace on the left, a scrollable list of user-defined features or fragments in the middle, and buttons on the right.

   When the dialog box opens, it shows all user-defined features that have been previously defined and added to the dictionary.

   When you select a feature in the scrollable list, it is displayed in the workspace of the dialog box.

2. Select the Functions Only button to display only functions in the scrollable list.

3. Select the Fragments Only button to display only fragments in the scrollable list.

4. Select the Functions & Fragments button to display fragments and functions in the scrollable list.

5. In the scrollable list, select the feature to be deleted. You can delete only one feature or fragment at a time.

6. To delete the selected feature, select the Delete button.

7. When you have selected and deleted the features you want, dismiss the dialog box by selecting the Return button.

   The dialog box disappears, and the feature is added to the Dictionary.

8. Check that the deleted feature has been removed from the Feature Dictionary.

9. Save your StockroomDB before you exit in order to preserve the changes to the Feature Dictionary.

For more details, see "To Display, Delete, Register, and Unregister Individual Conformers."

Generate Conformational Model

In the Generate Conformational Model dialog box, fill in the fields according to how you want the conformers generated:

• Maximum Number of Conformers to generate.

• Fast or Best Quality generation.

• Enter the Energy Range for the conformers.

• If you are generating conformers for more than one compound, the generation must be set up as a background process. If you want the background job to run on a machine other than the one you are using, select the Job Options- button and fill in the Job Options dialog box as described in To Set Up A Background Process.

• Conformers for a single compound can be generated within Catalyst or as a background process.

If the process runs within Catalyst, the conformers are automatically added to the compound. If the process runs in the background, you must use the Process Information command of the Data menu in the Stockroom to check on the status of the operation, and to retrieve the conformers when the generation process is finished. You also can use this command to cancel a running process. For more information on using the background process control functions, see the description of the "Process Information command."

To see the conformers that were generated, use the Show Conformational Model command. For a more detailed discussion of how to generate conformers, see "How to Generate Conformers."

Constraints Menu

Select a command:

The Constraints menu provides commands for defining excluded volumes, constraints, and geometric objects.

Add Excluded Volume

For more details about how to add an excluded volume, see "To Add Excluded Volumes."

Define Constraint

• Location - to set the name, radius and coordinates of a location constraint, select one point object (such as an atom)
• Distance - to set the name, and the minimum and maximum length of a distance constraint, select two point objects or a point and a plane
• Angle - to set the name, and the minimum and maximum value of an angle constraint, select three point objects
• Torsion - to set the name, and the minimum and maximum value of a torsion angle constraint around an axis, select four point objects

1. Select the objects to be constrained.
   See the list above for the objects to select.

2. Select the Define Constraints command from the Constraints menu, and then select the type of constraint you want (Location, Distance, Angle, Torsion) from the popup menu.

   Note that you also can use the Set Constraint Tolerance button in the Toolbox instead of the menu command, which automatically brings up the appropriate dialog box, depending upon the number of objects you have selected.

   A Constraint Tolerance dialog box appears that is appropriate to your selections, with a default name and tolerance range. A highlighted symbol for the constraint is displayed in the workspace.

3. Enter new values for name and tolerance in the dialog box, if desired.

4. Select the OK button to implement the changes and dismiss the dialog box, or select the Apply button to implement the changes and keep the dialog box on the screen.

Define Geometric Object

The geometric objects available to define constraints are:

• Centroid computes and displays the geometric centroid of the selected objects.

• Vector defines a vector from the first atom or feature selected (tail) to the second atom or feature selected (head).

• Hydrogen Bond Donor defines a hydrogen bond donor at a selected atom specification location.

• Hydrogen Bond Acceptor defines a hydrogen bond acceptor at a selected atom specification location

• Best-Fit Plane computes and displays for a set of selected hypothesis features the best fit plane and its normal vector.

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