P450 Site of Metabolism - Perform Calculation Panel (DEPRECATED)

This panel has been deprecated. For CYP P450 inhibition, use IFD-MD instead.

 

 

In this panel you can set up and run a calculation to evaluate a set of ligands for the likely sites of metabolism by various P450 isoforms.

To open this panel, click the Tasks button and browse to ADME and Molecular Properties → Perform Calculation.

  • Using
  • Features
  • Additional Resources

Using the P450 Site of Metabolism - Perform Calculation Panel

The ligands must be properly prepared before you run the calculation: 3D structures with all hydrogens. If you have 2D structures, or SMILES strings for the structures, you can prepare them with LigPrep—see the LigPrep User Manual — Contents for details.

The prediction of the site of metabolism has two parts: assessment of the intrinsic reactivity to the 3A4 isoform using Hammett and Taft methodology, based on a training set of 300 ligands; and evaluation of accessibility of atoms in the ligand to the Fe atom in other isoforms, using induced-fit docking to ensure both ligand and receptor flexibility. The induced-fit docking run can take some time, so you should consider running it on multiple processors.

To run P450 site of metabolism calculations from the command line, you can use the following command. Run the command with -h for more information.

$SCHRODINGER/ifd

To write out input files, click the arrow next to the Settings button,

and choose Write (more...).

For information on command options, see ifd Command Help.

P450 Site of Metabolism - Perform Calculation Panel Features

Take ligands from option menu

Choose the structure source for the calculations.

  • Project Table (selected entries)—Use the entries that are currently selected in the Project Table.
  • Workspace (included entries)—Use the entries that are currently included in the Workspace, treated as separate structures.
  • File—Use the specified file. When this option is selected, the File name text box and Browse button are displayed.
File name text box and Browse button

Enter the file name in this text box, or click Browse and navigate to the file. The name of the file you selected is displayed in the text box. The file must be in Maestro format.

CYP Isoform option menu

Choose the cytochrome P450 isoform for which you want to assess the sites of metabolism of the input ligands. Three isoforms are available: 2C9, 2D6, and 3A4. For each isoform, the calculations that will be run are indicated on the option menu. Only the intrinsic reactivity is assessed for 3A4 because ligand-based models have been found to provide satisfactory predictions.. For the others, an induced-fit docking calculation is also performed.

Start button

Run the job. Opens the Start P450 Job panel, in which you can name the job, choose a host, and set the number of processors to use for Prime and for Glide, then start the job. If you are running a calculation for the 3A4 isoform, only the Job name text box is available.

Write button

Write the input file for the job (not available for 3A4), for running from the command line. Opens the Write P450 Job panel, in which you can name the job, choose a host, and set the number of processors to use for Prime and for Glide, then write the input file, which you can edit if you want to adjust the induced-fit docking protocol. When you click Write, a dialog box is displayed that explains how to run the job.

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