The following tutorials are intended as quick start guides to Orion.
An Orion Docking Workflow¶
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.
As the only modeler on the pyrrolamides optimization project, your role 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.
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 for hit discovery and lead optimization. In hit discovery or virtual screening, no molecules active against the target protein are known. Docking is used to identify possible active molecules in a large molecule database by examining their shape and chemical complementarity to the active site.
- Receptor: 3TTZ_A-07N_A_373_receptor – import from MMDS (see below)
- Initial ligands: pyrrolamides_3D.sdf – download the dataset below and upload to Orion
- Conformer database – generate from pyrrolamides_3D dataset (see below)
After completing this task, you will be able to:
- Upload datasets into Orion
- Run an OMEGA Floe
- Retrieve a receptor from MMDS
- 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
- Navigate to the Orion home page and create a project called “Docking Demo”.
By default, Orion switches to the new project automatically.
- Navigate to the Project Data page and upload the ligand file pyrrolamides_3D.sdf.
- Switch to the Workfloe page, select the Classic OMEGA Floe, and generate ligand conformers.
- The OMEGA Floe should complete in less than 3 minutes.
- To prepare the receptor, click on Data Sources, and then select MMDS.
- Select the 3TTZ (A) receptor and send it to Orion.
- Switch to the Project Data page:
- Verify that the 3TTZ_A-07N_A_373_receptor is now available in the Datasets list
- Click on the + icon next to the 3TTZ_A-07N_A_373_receptor name. This adds the receptor
- to the active dataset(s).
- 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 ligand, respectively.
- Generate the Binding Site view:
- Select receptor
- Select ligand
- Click Generate Binding Site View
- Examine the protein-ligand interactions.
- Luanch the Docking Floe: Switch to the Workfloe page and select the “Classic OEDocking” Floe.
- Enter docking inputs.
- Monitor the job
- 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
- Analyze Results.
- Examine Docked Poses.
Using Floe Editor¶
- From the Workfloe page, click on the Editor tab.
- Familiarize yourself with the Editor tools.
- Floes tab: Built-in Floes.
- Cubes tab: Building blocks of Floes.
Most Cubes have input port(s) and output port(s) except for the Dataset Reader (output port only) and the Dataset Writer (input port only) Cubes.
- Create a simple Floe to calculate XLogP.
- This Floe requires 3 Cubes:
- Dataset Reader Cube
- XLogP Calculator Cube
- Dataset Writer Cube
- Click the Cubes tab and use the Search box to find the Dataset Reader Cube. Note: Type “reader” in the Search box.
- Double click or drag-and-drop the Dataset Reader Cube into the workspace.
- Type “xlogp” in the Search box to find the XLogP Calculation Cube.
- Double click or drag-and-drop the XLogP Calculation Cube into the workspace.
- Type “writer” in the Search box to find the Dataset Writer Cube.
- Double click or drag-and-drop the Dataset Writer Cube into the workspace.
- Your workspace should now contain three Cubes: Dataset Reader, XLogP, and Dataset Writer Cubes.
- Connect Cubes by dragging from one port to another.
To see compounds that fail the XLogP calculation, add another Dataset Writer Cube to the failure port of the XLogP Calculation Cube.
- Save your XLogP Calculation Floe. Your Floe is now ready and should appear in the list of available Floes.