Dock Ten Million Molecules with Gigadock Warp and Analysis with FreeForm Consensus

In this tutorial, ten million molecules will be selected at random from a collection provided by OpenEye and docked to the heat shock protein 90 (HSP90) target using the Gigadock Warp Floe. The FreeForm delta G values for the top docked molecules will be calculated with the FreeForm Pose Floe, and a consensus hit list of the best docked scores and FreeForm delta G values will be generated with the Pareto Frontier Consensus.

Running all the floes in this tutorial will cost approximately $50 in Orion compute charges.

This tutorial uses the following floes:

Note

If you have not created a tutorial project or prepared the HSP90 heat shock protein 90 (HSP90) target (using crystal structure 1uyg) to create the hsp90_design_unit dataset, please go to the Preliminary Setup Tutorial before beginning this tutorial.

Dock Molecules to Site

Locate the Gigadock Warp Floe on the Workflows tab in the Floe page.

Click “Launch Floe” to bring up the Job Form and set the following parameters.

  • Output Folder: Use Tutorial/My Data/Gigadock Warp and Analysis with FreeForm Consensus as the path.

  • Job Cost Limits: Expand the Job Costs Limits parameter group to see these settings.

    • Email me if this job cost exceeds: $40

    • Terminate this job if the cost exceeds: $50

    Note

    This floe is expected to cost ~$25. These cost limit values are specific to the input of this tutorial. They will need to be higher if this floe is run with more than 10M input molecules or a larger active site than HSP90.

  • Inputs

    • Design Unit Or Receptor Dataset(s): Click the “Choose Input” button and use the Tutorial/My Data/Input Data/hsp90_design_unit with the protein prepared by the SPRUCE - Protein Preparation Floe in the Preliminary Setup Tutorial.

    • Input Conformer Collection: Click the “Choose Input” button. A Select Dataset modal will pop up. Follow the path Organization Data/OpenEye Data/Gigadocking Collections and select an appropriate collection for your needs. To run the most affordable example for this tutorial, select the smallest collection. Click the “Use Collection as Input” button.

  • Options

    • Hit List Size: 1000

Click “Start Job” to begin the floe. The job will take ~2.5 hours and cost approximately $25. Wait for the floe to complete before continuing with the tutorial.

Compute FreeForm Delta G of the Hit List Molecules

Locate the FreeForm Pose Floe on the Workflows tab in the Floe page.

Click “Launch Floe” to bring up the Job Form and set the following parameters.

  • Output Folder*: Use Tutorial/My Data/Gigadock Warp and Analysis with FreeForm Consensus as the path.

  • Inputs

    • Input Dataset: Click the “Choose Input” button and use the Tutorial/My Data/Gigadock Warp and Analysis with the FreeForm Consensus/Gigadock Warp Hit List dataset output from the Gigadock Warp Floe.

  • Outputs

    • Output Dataset: Enter Gigadock Warp Hit List with FreeForm Delta G into the box.

Click the “Start Job” button at the to start the floe. The job will take roughly 45 minutes to run and cost about $25.

Compute Consensus of Docking Score and FreeForm Delta G

Locate the Pareto Frontier Consensus Floe on the Workflows tab in the Floe page.

Click “Launch Floe” to bring up the Job Form and set the following parameters.

  • Output Folder: Use Tutorial/My Data/Gigadock Warp and Analysis with FreeForm Consensus as the path.

  • Inputs

    • Input Dataset: Click the “Choose Input” button and use the Tutorial/My Data/Gigadock Warp and Analysis with FreeForm/Consensus/Gigadock Warp Hit List with FreeFrom Delta G dataset output from the FreeForm Pose Floe in the previous step.

    • Consensus Field(s) with Low Values Preferred: For this tutorial, use Chemgauss4 and FreeForm Pose Delat G.

      Enter *Chemgauss4 into the box. Then click the “Add More” button and enter FreeForm Pose Delta G in the new box that appears.

      Note

      Capitalization and spacing are important when entering these values.

The floe will take just a few minutes to run and cost less than $1.

View Results

To see the docked molecules and the receptor in the 3D Viewer on the 3D & Analyze page, you first need to activate the datasets.

Navigate to the Data page from the blue navigation bar.

In the My Data folder, select the Gigadock Warp and Analysis with FreeForm Consensus subfolder.

  1. In the ‘Show’ drop-down menu, be sure that the Datasets option is selected.

  2. Locate the Gigadock Warp Design Unit dataset. Make it active by clicking on the white circle with the plus symbol which will then become a green checkmark.

  3. Do the same thing with the Pareto Frontier Consensus dataset.

  4. These datasets should appear in the ‘Active Datasets’ drop-down. If other datasets are active, you can deselect them in the list or click the “Clear All” button.

For more detailed information on how to navigate the features in Orion, please see the User Guide, in particular the 3D & Analyze page and 3D Viewer.

Next, switch to the 3D & Analyze page and select the 3D Modeling layout.

  1. In the All Data tree, expand the Gigadock Warp Design Unit dataset and then expand the record under the design unit 1UGY(A) > PU(A-1224). Then click the dot next to it. The dot will turn green, and the DU will be visible in the 3D Viewer. You can visualize various parts of the DU by clicking the checkmark next to the component.

  2. Click the blue M badge next to the DU. It will grey out.

  3. Click on the first molecule under Gigadock Pose Clustered Hit List.

You should now see the first docked molecule in the context of the active site. Use the up and down arrows to select the next or previous docked structure.