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Create a QSAR database with Molecular Modeling Pro 5

In this tip sheet we will create a database of 979 compounds substituted at five different positions. The database will be created automatically from a substructure, which we will draw in. This database will be analyzed in the tip sheet "Analyzing a QSAR database with Molecular Analysis Pro". The data used comes from "QSAR studies of the fungitoxic properties of phenethyl 1,2,4-triazoles" (Pesticide Biochemistry and Physiology 30: 199-213 (1988)).

• 1. Draw in the substructure to be used. We will draw the phenethyl 1,2,4-triazole substructure. Click on the Rings button at the left. Choose triazole from the list. Click on the nitrogen without a double bond and carbon is added. Center the molecule. Click on the carbon just added to add another carbon. Click on the Rings button again and select phenyl from the list. Click on the last carbon you drew, and click on one of the atoms on the benzene ring to join the two structures. Double click on the hydrogen button to add hydrogens to the substructure. If the structure is vertical on the screen go to the Rotate menu and choose "Z". The default angle of rotation is 90 degrees and this is what we want, so hit the Done button. Click on the Change button. Click on the "C" button. We will now change one of the hydrogens on the carbon atom next to the phenyl ring to carbon. Click on the Change button on the left. Click on the C button on the left. Click on one of the hydrogens on the carbon next to the benzene ring. While still in change mode, change the other hydrogen on this carbon to carbon also. Now we are going to make one of the carbons part of a cyano group. Click on the Add button. Click on the 3 button Click on the N button. Click on one of the two carbons we just created. Click on the H button twice again to add the hydrogens. Minimize the structure with MM2 (Geometry menu/Minimize).
• 2. In this step we will create the first 78 molecules of the database with substitution on the methyl group attached to the carbon adjacent to the phenyl ring. Select "Save Database" from the File menu. Select "Make QSAR database" from the submenu. Click on a hydrogen on the methyl group attached to the carbon adjacent to the phenyl. Select the directory to save the database and connection tables to. c:/temp might be a good choice. Give the database a name and hit the Save button. For the first three letters of the Macromodel filename, type in HHH. When it asks the name of the building block structure type in something descriptive like CN_Phenethyl_Triazole_HHHC. When it asks if you want to create indicator variables say yes. We are going to create 5 indicator variables. Indicator 1 will indicate chlorine at the para phenyl position, indicator 2 will indicate fluoro at the para phenyl position, indicator 3 will indicate chloro at the ortho position, indicator 4 will indicate cyano in place of the hydrogen on the carbon adjacent to the phenyl ring, and indicator 5 will indicate that the methyl group we are substituting on is replaced with an oxygen. The values for this pass through the database for the indicator variables are 0, 0, 0, 1 and 0. The database of 78 will then be automatically created. Say no when it asks if you want to open the database.
• 3. We are repeating step 2 now for para-chloro substitution. Change the hydrogen at the para position to chlorine. Click on change, click on Cl, then click on the hydrogen at the para position. Now run the "Make QSAR database" routine again. Click on the same hydrogen on the methyl group as last time. We still do not want to modify a second site. Choose the same database name as last time. When it asks if you want to delete the old database, click on No - we want to merge them. Choose a different set of three letters for the MACROMODEL filenames or it will overwrite the old connection tables. I chose ClH this time. Give the building block a different name too that reflects the addition of the chlorine. The indicator variable values this time are 1, 0, 0, 1 and 0. Do not open the database.
• 4. - 12. We are going to repeat this process 9 more times.
• Next we are going to change the chlorine to fluorine. The indicator variable values are 0, 1, 0, 1 and 0.
• The fourth pass: Change the fluorine back to hydrogen. Change the methyl group to oxygen. The indicator variable values are 0, 0, 0, 1 and 1
• Fifth pass: Change the para position to chloro (the methyl group remains changed to oxygen). The indicator variables are 1, 0, 0, 1, 1.
• Sixth pass: Change the para position to fluorine. The indicator variables are 0, 1, 0, 1, 1.
• Seventh pass: Change the para position to chlorine. Change the ortho position on the phenyl ring to chlorine. Add hydrogens and minimize The indicator variables are 1, 0, 1, 1 and 1.
• Eighth pass: Change the oxygen back to methyl. The indicator variables are 1, 0, 1, 1 and 0.
• Ninth pass: Delete the cyano group (triple bonded nitrogen and the carbon it is attached to). The indicator variables are 1, 0, 1, 0 and 0.
• Tenth pass: Change the methyl group to oxygen. The indicator variables are 1, 0, 1, 0, and 1.
• The eleventh and final pass: Delete the chlorine at the ortho position. Click twice on hydrogen to add them. The indicator variables are 1, 0, 0, 0, and 1.
• Look at the database this time and see if you got all those indicator variables right.
• Note that the structures created by this database are not necessarily optimized, as there can be quite a bit of atom-atom overlap. Because of this MMP only creates calculated molecular properties that do not rely on 3-D structure. The substituent (not molecular) properties are from tables of values from the literature. It is possible to optimize the geometry of all of these molecules at once by selecting "Minimize all molecules in a directory" from the Geometry menu. This will take some time for the 979 molecules in this database. It might be a good over-night job.
• If you want to continue with the actual QSAR analysis, go to the next tip sheet, "Analyzing a QSAR database with Molecular Analysis Pro".
• If you would like this database to be loaded by default every time you turn on Molecular Modeling Pro do the following. Select "Initialize Links" from the File menu. Check "Open in database mode" and put the name of the file in the "Default database file:" text box. Note that the QSAR database creation tool always creates a database file in Molecular Analysis Pro format with the file extension ".csv".
• If you make a mistake that is added to the database, then you have several choices about how to eliminate the mistake.
  • 1) Start over if it is near the beginning of the creation of the database.
  • 2) Use the database Editor in MMP and delete the rows one at a time. Save the data.
  • 3) Use the Spreadsheet editor in MAP and delete a block; or use the file cards view and delete one at a time.
  • 4) If it is only one indicator variable that is wrong, then use the spreadsheet view in Molecular Analysis Pro. Change the first instance of the mistake. Then use the Fill Down menu item on the spreadsheet editor's Edit menu to change the other values.
  • 5) If you are more comfortable with EXCEL, then read the csv file into EXCEL and save it after making the changes as in #4.