Combi-Chem

3a. Library building

Building a benzodiazepine library

Note

2.   Open the Analog Builder control panel

Go to the LIBRARY CONSTRUCTION card located in the COMBI-CHEM I deck of cards and select the Analog Builder menu item.

This opens the Analog Builder control panel.

3.   Load a core structure

Go to the main Visualizer control panel and select the File/Load Model... menu item. Use the file browser in the Load Model control panel to select and load the file Cerius2-Resources/COMBICHEM/core-structures/benzo.msi.

This loads a benzodiazepine core.

Note

You now choose four attachment points.

To duplicate the example log script, you need to select atoms 19, 20, 23, and 10 as attachment points.

To see the atom numbers, go to the main Visualizer control panel and change the NO LABEL popup to NUMBERS.

This displays the atom numbers of the core model.

4.   Define the R groups on the core structure

In the upper right corner of the Analog Builder control panel, select the R-group tool. Go to the Cerius2 Models window and pick atoms 19, 20, 23, and 10 in that order.

If you accidentally create an R group attachment point that you do not want, you can get rid of its definition by making it the current R group, then clicking the Delete R Group button in the Analog Builder control panel.

You may now change the NUMBER popup back to NO LABEL.

The R group labels now appear on the model. The current R group list is shown in the right list box in the Analog Builder control panel, which is now labeled R4. The lists themselves are initially empty. Switching between R groups is done by using the arrows under the R group list box.

Use the arrows under the empty R group list to switch to R1.

To specify fragments for this R group, you need to change the To popup from All R Groups to Current R Group. This allows you to make independent substituent selections for each R-group attachment point. (You set this to All R Groups if you want to define identical substitution patterns for all attachment positions.)

Change the To popup (underneath the R group list box) from All R Groups to Current R Group.

5.   Define the list of R groups (substituents) for the R1 R-group attachment point

To specify fragments for this R group, first select fragments from the current fragment directory, which is displayed in the left list box in the Analog Builder control panel. The Current Set of R-groups at the top of the panel should be set to: ...Resources/COMBICHEM/fragments/organic_frags.sd Select these five fragments from the default list: hydrogen, benzyl, ethyl, methyl, and t_butyl. Now add the currently selected items from the current fragment directory to the R1 group list by clicking the arrow tool located between the list boxes.

You can correct your selections by deselecting fragments, which is easily done by control-clicking on a selected fragment. To start fresh on a new selection, click the Deselect All Fragments pushbutton below the R group directory list.

The five selected fragments are now shown in the R1 list.

6.   Define the list of R groups for the R2, R3, and R4 attachment points

Switch to the R2 definition by using the arrows under the R group list. Select the following three fragments from the default list: hydrogen, benzyl, and methyl. You can just control-click again on ethyl and t_butyl to deselect them. Now add these items from the current fragment directory to the R2 group list by clicking the arrow located between the scrolling lists. Now switch to R3 definition. Select the following six fragments from the default list: hydrogen, benzyl, ethyl, methyl, phenyl, and t_butyl. Now add these to the R3 group list. Switch to R4 definition. Select all the fragments from the default list by clicking the Select All Fragments pushbutton under the R group directory list box. Now add these to the R4 group list.

7.   Perform a diverse R group selection for R4

Now click the Select Diverse... button under the R4 list box. The Select Diverse Fragments control panel opens. You should select 8 fragments from the Current R Group using the MaxMin Diversity Measure. Once you have set the proper options in the Select Diverse Fragments control panel, click the SELECT pushbutton.

This automatically loads the complete set of fragments in a study table, calculates the default set of descriptors, and selects eight frag ments from the complete list.

After the process is complete, you can close the empty Study Table control panel and the Select Diverse Fragments control panel.

You should now remove the unselected fragments from the R4 group definition.

To do this, click the Remove Unselected pushbutton under the R4 list box.

Only the eight selected fragments remain in the R4 list box.

You can now examine all four R group lists by using the arrows under the R group list box.

This core structure with R groups defines the analogs to be generated. The current definition would create 720 analogs (5 x 3 x 6 x 8). This information is posted under the GENERATE ANALOGS pushbutton in the Analog Builder control panel.

8.   Save this combinatorial library definition

Select the File/Save Model... menu item on the main Visualizer control panel. Keep the save format as MSI and save the file as benzo_lib.msi.

Later, you can read the file back in and use the Analog Builder control panel to view the R groups and construct the analogs with different substituents and defaults.

9.   Set the Analog Builder preferences

Click the Preferences... pushbutton in the bottom left of the Analog Builder control panel and set the preferences.

Click Append Analogs to SD File and uncheck all boxes under QSAR Study Table and Diverse Fragments Selection.

Note

10.   Generate the analogs

Click the GENERATE ANALOGS pushbutton in the Analog Builder control panel.

This automatically generates the 720 possible combinations. The new analogs are by default loaded into the Model Manager. The file benzo.sd also contains the new analogs. This building step takes less than two minutes on an Indigo2 R10000 work station.

In future experimental runs you can change these defaults with the Analog Builder Preferences control panel.

After the process finishes, you can view any analog by making that model current in the Model Manager. Go to the Visualizer's Model Manager and click the diamond to the left of the desired name in the scrolling list of models.

Note

11.   Finishing this part of the tutorial

When you are finished viewing analogs, set the current model back to benzo.