of WODCA to the Design
of a Combinatorial Library
- The following example demonstrates the application of WODCA to
the design of a library of 1-phenyl-3,5-dimethylpyrazole compounds
(see Figure 1). Before we go into the details of the process for
planning this library, an overview of the individual steps is given.
Start WODCA by calling the WODCA start script
Define a representative compound of your library by starting the
CACTVS Molecule Editor from the
context menu of WODCA's structure
display and export it into WODCA.
Build a new synthesis tree by exporting the target compound to the
CACTVS Synthesis Planner. This can
be also performed within the context
menu of WODCA's structure display.
Choose a disconnection
strategy and perform a strategic
bonds search to dissect the target compound into suitable
Cut a strategic bond that has a high rating to generate
suitable synthesis precursors.
Export the precursors generated by WODCA to the CACTVS
Define substructures for each of the starting materials by defining
open sites at those positions where the precursor should be
generalized. Then perform substructure searches.
Search for a suitable synthesis of a library of compounds. This
involves: Repeat step 4 to 8 with the precursor compounds until a
promising synthesis plan has been developed which is based on
available starting materials from the catalog of chemicals and which
allows to build a library with a large number of compounds.
Figure 1: The lead structure of
The Synthesis Planning of a Library of
- The following screenshots demonstrate the individual steps which
are necessary to build a synthesis plan for the lead structure
(Figure 1) of the library. The numbered headlines correspond to the
individual steps which are described in the introduction to this
1. Start WODCA
- Call the start script
wodca.sh from a UNIX shell.
This provides the starting screen of WODCA as shown in Figure 2.
Figure 2: WODCA's starting screen
2. Input the Target Compound
- WODCA needs a completely defined target structure without any
open sites or R-groups to plan the synthesis of a combinatorial
library. Thus, a representative compound of this lead structure has
to be given. Use the following simple rules to transform a general
lead structure (Markush structure) into a specific compound:
- Figure 3 demonstrates this for the 1-phenyl-3,5-dimethylpyrazole
lead structure of Figure 1. For the R1-group there are no
restrictions on the kinds of the substituents. Thus, hydrogen atoms
are set for the five positions of the R1-group at the aromatic ring
system. The R2-group and the R3-group represents alkyl or aryl
groups which are replaced by methyl groups.
Figure 3: Definition of a simple representative
of the lead structure
Molecule Editor is needed to input the target structure. If this
molecule editor has not yet been started then click on the entry
Tools in WODCA's menu bar, pull it down and click on Launch
Molecule Editor. Another possibility is given by the use of the
context menu in WODCA's structure
display. Select the command Define New Target .... .
After a few seconds the CACTVS
Molecule Editor window appears. It allows the drawing of a new
structure just with the mouse. It is not necessary to draw hydrogen
atoms into your target structure since they will be added
automatically to open valences. Once the target structure has been
drawn it has to be transferred into the structure display of WODCA's
main window. In order to achieve this, click on the File
entry (Figure 4: (1)) in the
menu bar of the CACTVS Molecule Editor, pull it down and click on
the Export entry (Figure 4: (2)).
The chemical structure is then automatically transferred into WODCA
and the molecule editor window will automatically be minimized to an
Figure 4: Export of a molecule from the CACTVS
Molecule Editor into WODCA
3. Build a Synthesis Tree
- In order to create a graphical scheme of the synthesis plan
generated in this session you have to export the target compound to
Synthesis Planner. This can be performed with the context menu
structure display (Figure 5: (1)).
The context menu appears after pressing the right mouse button in
structure display . Select the entry Start New Synthesis
Plan ...(Figure 5: (2)) to
perform the export of the target compound into the CACTVS Synthesis
Planner. It is not necessary to separately start the CACTVS
Synthesis Planner, because it is started automatically after calling
the menu command.
Figure 5: Transfer of the target compound into
the CACTVS Synthesis Planner
The target compound is then displayed in the CACTVS Synthesis
Planner as the top of the synthesis tree (Figure 6).
Figure 6: Display of the target compound in the
CACTVS Synthesis Planner
4. Choose a Disconnection Strategy and Perform a Search for
- The analysis of strategic bonds is started with the
disconnection strategy Carbon-Heteroatom Bonds to find
suitable precursors for the target structure. Therefore, we go to
the Disconnection menu in WODCA's menu-bar (Figure 7: (1))
and click on the Strategic Bonds ... command. The strategic
bonds window of WODCA appears (Figure 7: (2)).
We choose the disconnection strategy Carbon-Heteroatom Bonds on
the right-hand side of the window (Figure 7: (3))
and press the Search button (Figure 7: (4)).
WODCA perceives two strategic bonds (Figure 7: (5)).
One bond is rated with the maximum value of »100«, a
second bond is rated relative to this bond with the value of »87«
which is also quite favorable. Having two highly rated strategic
bonds promises to give suitable precursors.
Figure 7: Evaluation of strategic bonds
5. Cut a Strategic Bond
- You can now follow the sequence of strategic bonds suggested by
the rating of WODCA or you can change this order. Furthermore, it is
possible to require several bonds to be simultaneously broken. The
disconnection of strategic bonds directly leads to synthesis
precursors, since WODCA adds suitable atoms to the open valences
obtained on heterolysis of a bond. In our example, we decide to
follow the suggestions of WODCA and break both bonds at the same
time. Therefore, we insert the ranks of these two bonds into the Set
of Bonds entry (bond 1 and bond 2 in our example), separate the
ranks by an empty space and then press the Cut Bond button
(Figure 7: (6)).
WODCA now generates two precursors for the target structure:
phenylhydrazine and 2,4-pentanedione in its enol form (Figure 8).
Figure 8: Dissection of target compound
The tautomerization of this enol form to its more stable keto form
is performed via the context menu of the structure display (press
the right mouse button on the Precursor(s) display, Figure 9:
(1)) and select the Tautomerize
Precursor command (Figure 9: (2)).
Figure 9: Tautomerization of precursors
6. Export of Precursors to the CACTVS Synthesis Planner
- Now, we attach both precursors to our synthesis plan. This is
also performed with the help of the context menu in the strategic
bond display (press the right mouse button on the Precursor(s)
display, Figure 10: (1),
and select the command Attach to Synthesis Plan, Figure 10:
Figure 10: Adding synthesis precursors to the
A second level is built at the synthesis tree handled by the CACTVS
Synthesis Planner. One of the precursor compounds in this new level
is marked as active (yellow box). The active precursor is always
synchronized with the compound in WODCA's Strategic Bonds
display. Therefore, after the attachment of the precursors to
the synthesis tree, one compound - in our case 2,4-pentanedione - is
automatically exported to the WODCA main program and an identity
search is automatically performed by WODCA (Figure 11).
Figure 11: Building a synthesis tree
8. Substructure Searches
- Now, we want to perform a substructure search with the active
compound loaded in WODCA. Therefore, we go to the Searches menu
in WODCA's menu bar (Figure 12: (1))
and click on the Substructure Search ... command (Figure 12:
Figure 12: Performing a substructure search in
The window of the CACTVS Substructure Search tool appears
with the query compound loaded in the structure display. (Figure 13:
Figure 13: The CACTVS Substructure Search tool
This representative precursor for our lead structure is used to
define a substructure with open sites. We delete hydrogen atoms at
all positions where a generalization of the structure to R groups is
desired in order to create a suitable substructure of our
phenylhydrazine precursor. Therefore, it is necessary to switch the
CACTVS Substructure Search tool from drawing mode into eraser
mode by pressing the rubber icon in the upper right corner of the
window (Figure 14: (1)). Then,
we click once with the left mouse button on each hydrogen atom
marked with a red box to delete it and to define an open valence
(Figure 14: (2)). Afterwards, we
press the Search button (Figure 14: (3))
to perform the substructure search in the catalog of chemicals.
Figure 14: Defining the substructure query
The substructure prepared as shown in Figure 14 provides 23 hits in
the FLUKA catalog that contains 16,769 compounds. This is indicated
in the Match List icon of WODCA's main window (Figure 15:
(1)). We click once on the Match
List icon with the left mouse button to display these hits. Now,
all chemical compounds are transferred to the CACTVS Structure
Browser (Figure 15: (2))
which is started automatically.
Figure 15: Display of a match list of
phenylhydrazine derivatives from a catalog of chemicals
In a similar manner, a substructure search for generalized
variations of the 2,4-pentanedione-precursor is performed. In a
first step, the diketone precursor is activated by a single mouse
click in the synthesis tree and exported to the WODCA main program
(Figure 16: (1)). In a second
step, the substructure search is initiated by the Searches
menu in WODCA's menu bar (Figure 16: (2)).
To find out which 1,3-diketones with alkyl or aryl substituents at
position 1 and 3 are contained in the catalog of available starting
materials, open all sites at the two methyl groups of the
2,4-pentanedione precursor by deleting all hydrogen atoms marked
with a red box (Figure 16: (3)).
This corresponds to putting R2 and R3 groups
at the end of the 1,3-diketone substructure, but it already
restricts these R2 and R3 groups to have
carbon atoms at their junction to the 1,3-diketone substructure.
After pressing the Search button (Figure 16: (4))
the substructure search in the catalog of chemicals is performed.
Figure 16: Substructure search with the
The result of this substructure search is shown in Figure 17. Twenty
1,3-diketones are found in the catalog of chemicals. Click on the
Match List icon in WODCA's main window to view these hits
(Figure 17: (1)). The CACTVS
Structure Browser is then automatically started to display all
the structures from the match list (Figure 17: (2)).
Figure 17: Display of a match list of 1,3-diketone
derivatives from a catalog of chemicals
If one is also interested in acyl derivatives, in carboxylic acids,
or in amides the substructure query has to be changed. It is
possible to define a set of atom types which are allowed or which
are forbidden for a certain position in the substructure query. This
can be done by means of atom
lists. The following example shows the definition of a
substructure query which is qualified to find such compounds in a
catalog of chemicals by a substructure search.
Again, the diketone precursor is activated by a single mouse click
in the synthesis tree and is thereby exported to the WODCA main
program (Figure 18: (1)). The
substructure search is initiated (Figure 18: (2))
and the substructure query is defined. In a first step, the CACTVS
Substructure Search tool is switched to »eraser mode«
(Figure 18: (3)) and all
hydrogen atoms marked with a red box are deleted with a single mouse
click (Figure 18: (4)).
Figure 18: Preparing a new substructure query
After the hydrogen atoms are deleted, the atom list for each
substituent in 1,3-position has to be defined. Therefore, the CACTVS
Substructure Search tool is switched back to »pencil
mode« (Figure 19: (1))
and a double click on one of the carbon atoms marked with a red box
is performed (Figure 19: (2)).
This opens a dialog box for the specification of atom types. Set the
Atom Type to List and enter »!C« to
exclude carbon atoms from the list of elements which are allowed at
the atom position considered (Figure 19: (3)).
Then, press the Set button to close this dialog box (Figure
19: (4)) and repeat this
procedure for the other carbon atom to finish the definition of the
It is also possible to exclude more than one elements from an atom
list, e.g. by specifying »!O !N«. If more than one
element is defined, the element symbols have to be separated by an
Figure 19: Specification of atom lists
An atom list is indicated by the letter L instead of an atom
symbol (Figure 20: (1)). The
substructure search is then started by pressing the Search
button (Figure 20: (2)).
Figure 20: Substructure query with atom lists
The result of this substructure search is displayed after a single
mouse click on the Match List icon in WODCA's main window is
performed (Figure 21: (1)). The
CACTVS Structure Browser is then started to display all 32
structures from the match list (Figure 21: (2)).
Figure 21: Result of a different substructure
- Last change: 2000-06-29