Tutorials

The following tutorials are intended as quick start guides to Orion.

An Orion Docking Workflow

This tutorial shows use of a sequence of Floes to perform a project. It also shows how to use an assortment of user interface features, such as examination of binding sites.

DNA gyrase (GyrB) and topoisomerase IV (Topo IV) are clinically validated targets for the treatment of resistant bacterial infections. In a study carried out at a big Pharma, pyrrolamides were shown to exhibit antibacterial activity by competing with adenosine triphosphate (ATP) in DNA gyrase and Topo IV.

In this simulation, your role, as the only modeler on the pyrrolamides optimization project, is to guide the medicinal chemists in their design decisions: they want suggestions on what to synthesize next. Your ultimate goal is to help them synthesize the depicted compound.

Target compound

You will explore docking in this retrospective study. In the drug discovery process, structure-based methods such as docking—the lock-and-key concept where the protein is the lock and the ligand is the key—use the structure of a target protein to discover hits and lead optimize leads. In hit discovery or virtual screening, no molecules are known that are active against the target protein. Docking is used to identify possible active molecules in a large molecule database, by examining their shapes and chemical complementarity to the active site.

Datasets

• Initial ligands: pyrrolamides_3D.sdf – download the dataset below.

• Receptor: 3TTZ_A_receptor – download the receptor below.

• Conformer database – generate from pyrrolamides_3D dataset (see below).

Download dataset of initial ligands

pyrrolamides_3D.sdf

Download receptor

3TTZ_A__receptor.oeb

After completing this task, you will be able to:

• Upload datasets into Orion

• Run an Omega Floe

• Retrieve a receptor from a database

• Identify the binding pocket

• Perceive protein-ligand interactions

• Run a (docking) Floe

• Analyze docking results in the Analyze page

• Perform a substructure search

• Add Property data to a spreadsheet

• Sort the data in a spreadsheet

• Export data

1. Navigate to the Orion home page and create a project called “Docking Demo.”

By default, Orion switches to the new project automatically.

2. Navigate to the Data (Project Data) page and upload the ligand file pyrrolamides_3D.sdf.

A dialog pops up showing that the upload is in progress, and then a conversion Floe runs quickly, producing a dataset from the uploaded file. The end result is shown here:

The icon next to the job details, on the upper right () shows the Floe that produced the dataset:

Here, a File to Record Converter cube uploaded and converted the ligand file, and then it fed its output to the Dataset Writer cube.

3. Switch to the Floe (Workfloe) page, select the Floe OMEGA - 3D Conformer Ensemble Generation, and generate ligand conformers.

You will select the pyrrolamides_3D file as input to the Omega Floe.

Click on the name pyrrolamides_3D to select that file, and then click the icon to provide it as input to the Omega Floe. You can leave the other parameters with their default values and click the icon.

4. The Floe runs for only a few minutes, after which there is a new dataset—the set of conformers—in our data folder:

5. To prepare the receptor, click on the icon, and then select the file 3TTZ_A__receptor.oeb at the location to which you downloaded it previously. After another run of the conversion Floe, the receptor data are present in the project folder:

We have provided the receptor file as a download in this tutorial, but more typically you might click on the Sources (Data Sources) page and get a receptor from a database such as MMDS.

6. Generate a binding site.

   • Verify that the 3TTZ_A_receptor is now available in the Active Datasets list on the Data page

   • Click on the icon next to the 3TTZ_A_receptor name. This adds the receptor

     to the active dataset(s).

7. Go to the 3D Modeling page and examine the binding site.

• To make the receptor & ligand visible, click on the Show/Hide icons for the receptor and the ligand 07N(A), respectively.

8. Generate the Binding Site view:

   • With receptor selected

   • With ligand 07N(A) selected

   • Click the Generate Binding Site icon ()

   You can control elements of the displayed binding site wih the Binding Site Options dropdown. For example, you can uncheck Show Labels and then regenerate the binding site.

A view of the binding site

9. Examine the protein-ligand interactions. The auto-interactions icon () has a dropdown with additional display options.

Interactions and options

10. Launch the Docking Floe: Switch to the Floe page and select the Floe called “OEDocking - Dock into an Active Site for Virtual Screening.” You may need to do a search for “OEDocking” to bring up this Floe on the selection list.

11. Enter docking inputs.

Inputs to the docking Floe

The job typically completes in about 10 minutes.

13. Add docked poses to active datasets:

• Once the docking job is complete, click Project Data

• Add 3TTZ_A-07N_A_373_receptor to Active datasets

• Add pyrrolamides_3D_docked_into_3TTZ to Active datasets

14. Analyze Results.

    Go to the Analyze page. Make a scatter plot with Chemgauss on the Y axis and IC50 on the X axis.

To show a depiction of a molecule, you can scroll to it in the list in the bottom part of the Analyze page and click on the icon

Magnified depiction of a molecule

15. Examine Docked Poses.

    Go to the 3D page.

Background Information about Docking

Would you like to know more?

For more information about the Classic Docking Floe, see OEDocking–Dock into an Active Site for Virtual Screening.

For more information about the Classic Omega Floe, see the reference documentation about the Omega Floe used in this tutorial.

If you are doing more advanced work, in Python, you may also be interested in the theory of docking, as presented here.