3.
Isolate the ligand and pocket in 3D:
4. Color the ligand atoms using the System Manager:MOE | RHS | SiteView
MOE | RHS | SystemClick on the gray box next to "Ligand" to open the atom color panel.Color the ligand carbon atoms green:
5. Draw a Molecular Surface around the binding site:MOE | RHS | Surface | ReceptorClick on the background of the MOE Window to deselect the ligand atoms.6. Adjust the transparency of the pocket surface from the Surfaces and Maps panel:
Select the Quick Surface in the list and adjust the transparency of the front and back faces with the slider controls:MOE | RHS | Surface | Surfaces and Maps
Docking a Single Ligand
The atoms specified in the Receptor option will be considered when the ligands are docked, with binding poses focusedaround the atoms specified with the Site option. The site atoms might typically be dummy atoms created using the Site Finder application.The Protocols menu applies changes to the settings on the rest of the panel. It includes protocols for Rigid Protein Docking,High-Throughput Virtual Screening and Induced Fit Docking (where receptor sidechains are allowed to flex during refinementof the poses).In the first example we will use the default protocol - Rigid Protein Docking. This uses Receptor+Solvent for the Receptor , and Ligand Atoms for both the Ligand and Site . Ligand conformations are generated with the bond rotation method. Theseare then placed in the site with the Triangle Matcher method, and ranked with the London dG scoring function. The Retain option specifies the number of poses (30) to pass to the Refinement , for energy minimization in the pocket, beforerescoring with the GBVI/WSA dG scoring function.1. Open the Dock panel:MOE | Compute | Dock
2. Click Run to start the calculation.3. Click the SVL button at the top right of the MOE window to view progress reports in the SVL Commands window asthe calculation is running.
4. The docking results in dock.mdb will appear in the Database Viewer. The poses are ranked by the scores from theGBVI/WSA binding free energy calculation in the S field. The rmsd field shows the RMSD of the docking pose comparedto the co-crystal ligand position. The rmsd_refine field has the RMSD between the pose before and after refinement.5. Use the Database Browser to compare the docking poses to the ligand in the co-crystallized structure:
DBV | File | Browse…
6. The SiteView button will render the ligands in stick mode and hide the non-polar Hydrogens:MOE | RHS | SiteView
Creating a Pharmacophore Query.7. Use the arrows of the Database Browser to browse through some of the docked poses. Close the Database Browserand close the dock.mdb Database Viewer.
A pharmacophore query is created using the Pharmacophore Query Editor. A query consists of a set of constraints on thelocation and type of pharmacophoric features. It can be used with MOE Dock to either place the ligands into the site, or tofilter poses from another placement method.Rolipram makes two Hydrogen bonds with the receptor; between the two ether oxygens and the amide Nitrogen in thesidechain of Glutamine 443. The Contacts panel in the MOE Footer controls the display of these interactions.We will create a pharmacophore query with two features. First is a Acc2 projected Hydrogen bond acceptor feature placed onthe sidechain amide Nitrogen for Gln 443. Ligand poses will only be accepted if a Hydrogen bond acceptor atom in the ligandis in a suitable position to form a Hydrogen bond with the Nitrogen. Second is an Aro feature, matching the aromatic ringcentroid in the ligand.1. Open the Pharmacophore Query Editor:MOE | Compute | Pharmacophore | Query Editor…2. In the Pharmacophore Query Editor, press the button labeled R , (adjacent to the Scheme ) so that it becomes yellowas shown below.
This will annotate the receptor for creating receptor-based pharmacophore features.3. Select the cyan annotation point on the amide Nitrogen (see below) and click Feature in thePharmacophore Query Editor. 4. Select the orange annotation point in the center of the phenyl ring (see below) and click Feature in thePharmacophore Query Editor.
Two pharmacophore features in the MOE window
You have now created a pharmacophore query with a projected acceptor and an aromatic feature defined by the regions ofthe spheres shown in the MOE window.Two pharmacophore features in the Pharmacophore Query EditorDocking a Database of Compounds
1. Open the Dock panel:Next, we will dock a database of ligands to the receptor and filter the poses with the pharmacophore query.
MOE | Compute | Dock2. Select Virtual Screening from the Protocols menu.This will change the panel settings to those suitable for docking a large number of compounds. For example, refinementof the poses is disabled.
3. Set the Output database to dock2.mdb 4. Verify that the Receptor and Site pull-down menus are set to Receptor+Solvent and Ligand Atoms. 5. Pharmacophore will be set to Pharmacophore Query Editor by default.6. Set the Ligand pull-down menu to MDB File. Click Browse and select $MOE/sample/mol/1RO6_ligands.mdb as thedatabase of ligands to dock.7. Click Run to start the calculation. When the docking is finished, the docked poses and scores will be written to theoutput database.
8. Allow a few moments to complete the docking. When it is finished, close the Pharmacophore Query Editor and usethe database browser to compare the docking poses to the co-crystallized ligand already present in the MOE window:
9. The SiteView button will render the ligands in stick mode and hide the non-polar Hydrogens:MOE | RHS | SiteViewDBV | File | Browse…
As you browse through the docking database, you can compare the poses of Rolipram from the co-crystallized structure(green carbons) with the docked. Have a look at the displayed Hydrogen bond interactions between the ligands and thereceptor and note how they are preserved by most of the docking poses.
3.
Isolate the ligand and pocket in 3D:
4. Color the ligand atoms using the System Manager:MOE | RHS | SiteView
MOE | RHS | SystemClick on the gray box next to "Ligand" to open the atom color panel.Color the ligand carbon atoms green:
5. Draw a Molecular Surface around the binding site:MOE | RHS | Surface | ReceptorClick on the background of the MOE Window to deselect the ligand atoms.6. Adjust the transparency of the pocket surface from the Surfaces and Maps panel:
Select the Quick Surface in the list and adjust the transparency of the front and back faces with the slider controls:MOE | RHS | Surface | Surfaces and Maps
Docking a Single Ligand
The atoms specified in the Receptor option will be considered when the ligands are docked, with binding poses focusedaround the atoms specified with the Site option. The site atoms might typically be dummy atoms created using the Site Finder application.The Protocols menu applies changes to the settings on the rest of the panel. It includes protocols for Rigid Protein Docking,High-Throughput Virtual Screening and Induced Fit Docking (where receptor sidechains are allowed to flex during refinementof the poses).In the first example we will use the default protocol - Rigid Protein Docking. This uses Receptor+Solvent for the Receptor , and Ligand Atoms for both the Ligand and Site . Ligand conformations are generated with the bond rotation method. Theseare then placed in the site with the Triangle Matcher method, and ranked with the London dG scoring function. The Retain option specifies the number of poses (30) to pass to the Refinement , for energy minimization in the pocket, beforerescoring with the GBVI/WSA dG scoring function.1. Open the Dock panel:MOE | Compute | Dock
2. Click Run to start the calculation.3. Click the SVL button at the top right of the MOE window to view progress reports in the SVL Commands window asthe calculation is running.
4. The docking results in dock.mdb will appear in the Database Viewer. The poses are ranked by the scores from theGBVI/WSA binding free energy calculation in the S field. The rmsd field shows the RMSD of the docking pose comparedto the co-crystal ligand position. The rmsd_refine field has the RMSD between the pose before and after refinement.5. Use the Database Browser to compare the docking poses to the ligand in the co-crystallized structure:
DBV | File | Browse…
6. The SiteView button will render the ligands in stick mode and hide the non-polar Hydrogens:MOE | RHS | SiteView
Creating a Pharmacophore Query.7. Use the arrows of the Database Browser to browse through some of the docked poses. Close the Database Browserand close the dock.mdb Database Viewer.
A pharmacophore query is created using the Pharmacophore Query Editor. A query consists of a set of constraints on thelocation and type of pharmacophoric features. It can be used with MOE Dock to either place the ligands into the site, or tofilter poses from another placement method.Rolipram makes two Hydrogen bonds with the receptor; between the two ether oxygens and the amide Nitrogen in thesidechain of Glutamine 443. The Contacts panel in the MOE Footer controls the display of these interactions.We will create a pharmacophore query with two features. First is a Acc2 projected Hydrogen bond acceptor feature placed onthe sidechain amide Nitrogen for Gln 443. Ligand poses will only be accepted if a Hydrogen bond acceptor atom in the ligandis in a suitable position to form a Hydrogen bond with the Nitrogen. Second is an Aro feature, matching the aromatic ringcentroid in the ligand.1. Open the Pharmacophore Query Editor:MOE | Compute | Pharmacophore | Query Editor…2. In the Pharmacophore Query Editor, press the button labeled R , (adjacent to the Scheme ) so that it becomes yellowas shown below.
This will annotate the receptor for creating receptor-based pharmacophore features.3. Select the cyan annotation point on the amide Nitrogen (see below) and click Feature in thePharmacophore Query Editor. 4. Select the orange annotation point in the center of the phenyl ring (see below) and click Feature in thePharmacophore Query Editor.
Two pharmacophore features in the MOE window
You have now created a pharmacophore query with a projected acceptor and an aromatic feature defined by the regions ofthe spheres shown in the MOE window.Two pharmacophore features in the Pharmacophore Query EditorDocking a Database of Compounds
1. Open the Dock panel:Next, we will dock a database of ligands to the receptor and filter the poses with the pharmacophore query.
MOE | Compute | Dock2. Select Virtual Screening from the Protocols menu.This will change the panel settings to those suitable for docking a large number of compounds. For example, refinementof the poses is disabled.
3. Set the Output database to dock2.mdb 4. Verify that the Receptor and Site pull-down menus are set to Receptor+Solvent and Ligand Atoms. 5. Pharmacophore will be set to Pharmacophore Query Editor by default.6. Set the Ligand pull-down menu to MDB File. Click Browse and select $MOE/sample/mol/1RO6_ligands.mdb as thedatabase of ligands to dock.7. Click Run to start the calculation. When the docking is finished, the docked poses and scores will be written to theoutput database.
8. Allow a few moments to complete the docking. When it is finished, close the Pharmacophore Query Editor and usethe database browser to compare the docking poses to the co-crystallized ligand already present in the MOE window:
9. The SiteView button will render the ligands in stick mode and hide the non-polar Hydrogens:MOE | RHS | SiteViewDBV | File | Browse…
As you browse through the docking database, you can compare the poses of Rolipram from the co-crystallized structure(green carbons) with the docked. Have a look at the displayed Hydrogen bond interactions between the ligands and thereceptor and note how they are preserved by most of the docking poses.