[ Consensus Pharmacophore | Pairwise APF Score | APF Ligand Based Screen ]

The Atomic Property Fields (APF) superposition/alignment method was first reported by Maxim Totrov PhD (Principal Scientist - MolSoft) at the 2007 233rd American Chemical Society National Meeting, Chicago, IL USA and then published here. This section shows you how to:

• Generate a consensus pharmacophore from the APF fields.
• Calculate a pairwise APF score.
• Perform ligand-based screening using APF fields.

17.21.1 Consensus Pharmacophore

To generate a Consensus Pharmacophore based on APF fields use the Chemistry/APF Tools/Consensus Ph4 menu option.

Load and display two or more superimposed chemicals. You can superimpose the chemcials using APF fields as described here or using substructure superposition.

Select the ligands. You can select the ligands by clicking on them in the ICM workspace whilst holding down the CTRL key. Aleternative selection modes are described here.

Choose the Consensus Ph4 menu option. Chemistry/APF tools/Consensus Ph4.

Select the threshold for each property. For example, if the setting is 0.75 then the pharmacophore will be displayed ifthe property is found in 75% or more of the ligands.

Consensus is displayed as meshes. Each mesh can be displayed or undisplay in the ICM workspace.

17.21.2 Pairwish APF Score

To determine how well the APF fields of two chemicals match you can determine the Pairwise APF Score using the Chemistry/APF Tools/Pairwise APF Score menu option.

Load and display two superimposed chemicals. You can superimpose the chemcials using APF fields as described here.

Select the first chemical. Use the green selection to orange button to select the first chemical.

Select the second chemical. Double click the chemical in the ICM workspace to select it.

Choose the Pairwise APF Score menu option. Chemistry/APF tools/Pairwise APF Score

Check the selections are correct. Choose whether you wish to calculate the score based on all atoms or just the surface atoms.

The APF Pairwise Score is displayed in the terminal window. The score is also returned to r_out. Do not see the Terminal window? Go to Windows menu and check the Terminal box.

17.21.3 APF Ligand Based Screen - Screen SD file against template molecule(s)

This option allows you to perform a ligand-based screen using the Atomic Property Fields of superimposed chemicals. SD files are screened and the ligands are scored according to their fit into the APF field.

Independent Evaluation Reports High Accuracy of ICM APF Ligand Based Screening Compared to Other Software. In a 2010 publication by Giganti et al (Pasteur Institute, France) in the Journal of Chemical Information and Modeling ICM displayed the best performance in terms of molecular alignment and docking accuracy compared to four other software programs. The paper reports on the efficiency of MolSoft's Biased Probability Monte Carlo method which is good at sampling flexibility. You can read about the comparison here. The authors tested ICM-docking and the Atomic Property Field (APF) method. The APF method is described here: Totrov M (2008) Atomic property fields: generalized 3D pharmacophoric potential for automated ligand superposition, pharmacophore elucidation and 3D QSAR. Chem Biol Drug Des 71: 15-27

Read in and display the superimposed template chemicals. In this example we will use three aldose reductase crystal structures 1PWM, 2I17, and 1Z8A.

Select each chemical you wish to contribute to the APF fields. Select by double clicking on the chemical in the ICM workspace and hold down the CTRL key.

Choose the Screen SD file against template molecule(s) option. Chemistry/APF tools/Screen SD file against template molecule(s)

Select the SD database you wish to screen. Select the database in SD format you wish to screen and Select whether you want flexible rings to be sampled by checking the appropriate box. Select whether you want cis and trans conformations of double bonds to be sampled by checking the appropriate box. Select whether you would like to sample tautomers. A score for how well the ligand fits into the APF envelope can be generated. Select if desired. Scores <-100 are generally good and so you can filter out poor ligands using the Keep only Score < option. Select the Advanced button if you want the superposition to be weighted by occupancy of the atoms by checking the appropriate box. It is often desirable to preferentially superimpose parts of a ligand while ignoring other regions. This can be achieved by setting the occupancy to zero for regions you are not focusing on. See: command line manual http://www.molsoft.com/man/icm-commands.html#set-occupancy . You can also define the weights for lipophilic and polar matches.

A notification will be displayed when the screen is completed.Click OK and a hitlist table will be displayed.

A hitlist table will be displayed. You can sort the table by score and toggle the display on and off using the buttons in the L column.