[ Markush | Enumerate by Scaffold | R-Group Decomposition | Enumerate by Reaction ]

17.18.1 Create/Modify Markush

To create or modify a Markush Structure:

• Use the Molecular Editor to edit the scaffold as shown below.

• Close the Molecular Editor window by clicking on the cross in the top right hand corner and the changes will be submitted to the table.
• The sketch in the chemical spreadsheet is named "chem" by default. For this example we will rename it "scaffold". You can rename it by right clicking on the table tab and selecting rename.

Step 4: Create Markush Combinatorial Library

• Read in a table of substituents. For this example we will use an sdf file called combiDock_R1.sdf - this can be found in the ICM distribution (File/Open). If you cannot find this file please E mail support@molsoft.com and we will send it to you.
• Chemistry/Create Modify Markush and enter the data as shown below and press next.

• Enter the name of the table containing substituents for R1 and R2. In this example we will use the same table combiDock_R1 for R1 and R2 as shown below. You can use the drop down arrows to select the table you require.

• Once the tables are selected press Create and a new chemical table will be displayed with the markush structure annotated with the substituents for R1 and R2 as shown below.

17.18.2 Enumerate by Scaffold

To enumerate a library based on R-groups you first need to draw a sketch of the structure and display it in a chemical spreadsheet. To do this:

• Open up the ICM Molecular Editor.
• Draw the template structure with R-groups attached. Right click on an atom and select Element/R1, R2 ...

• In the Molecular Editor select File/Append to Table/New

The next step is to read into ICM or construct a table of substituents. You can read in an SDF, mol, smiles file or extract fragments. If you do not want the first atom of the substituents to be the attachment point you need to define the attachment point. Attachment points are automatically assigned when you extract fragments or you can define them manually by:

• Right click on the substituent sketch and select Edit Molecule
• Right click on the atom and select Attachment point.

Next enumerate the library

• Select the template structure (highlighted blue).
• Right click on the structure and select Chemistry/Enumerate R-groups or use the Chemistry menu and select Enumerate by Markush. If you use the menu option you will need to choose the table containing the scaffold from the drop down list of currently loaded tables. The index number refers to the row number in the scaffold table. In this example we only have one row containing the scaffold so the index number is 1.
• Select the R1, R2... table , labels and filters if necesary.

A new table will be produced called T_enum with the Template structure highlighted in red.

17.18.3 R-Group Decomposition

To decompose a library into fragments based on a Markush scaffold (opposite of R-group (Markush) enumeration):

• Read the sdf file you wish to decompose into ICM and it will be displayed as a molecular table.
• Chemistry/R-Group Decomposition and a window as shown below will be displayed.
• You now have two options on how to define the Markush scaffold. You can either 1). Draw it using the molecular editor and the smiles string will be added to the window shown below or 2). select a row of a prexisting table.

• Use the drop-down option to select the table you wish to decompose.
• If you have more than one R-group ICM can either generate a different table for each R-group or it can merge it into one single table whereby column will represent R1 and column two R2 .... This option is useful if you want to generate a SAR table with a column of activity data next to the R1 and R2 columns (see below).
• If you check the box "Auto Add Missing R Groups" then unique R-groups will be extracted from the scaffold where hydrogens can be attached.

17.18.4 Enumerate by Reaction

Reactions can be drawn using the ICM Molecular Editor. Reactants should be drawn side-by-side (no + sign is necesary) and separated from the product using the arrow. See example shown below:

This example is available in the ICM distribution as example_reaction1.icb. The reaction is the Hantzsch Dihydropyridine (Pyridine) Synthesis. This reaction allows the preparation of dihydropyridine derivatives by condensation of an aldehyde with two equivalents of a �-ketoester in the presence of ammonia. Subsequent oxidation (or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may also be decarboxylated to yield the corresponding pyridines.

In this example we have two reactants therefore it is necesary to have two reactant substructure tables loaded into ICM. ICM will match the substructure drawn in the reaction with the chemicals in thereactant table.

reactant 1 table:

To apply a reaction:

• Chemistry/Enumerate by Reaction.
• In this example (example_reaction1.icb) we already have the reaction drawn in a chemical table. Therefore select the Choose Table With Reaction. If you would like to draw a new reaction select Draw New Reaction.
• Enter the name of the table containing the reaction. If you have more than one reaction drawn you can select the row using the index option.
• Click OK and then you will be asked to enter the Reactants. Select the reactant tables from the drop down arrow for Reactant 1 and Reactant 2.
• You can transfer information to the reactant table by selecting columns in the Labels section.
• Unused reactants can be marked.
• Select what you want to do with multiple matches.

A table of Products will be then displayed in a table called T_out. Columns in T_out labeled "rct" display which reactants were used to build the product.