FastROCS Plus with Freeform Analysis

In this tutorial the the Enamine REAL collection will be search for molecules that best match the 3D shape and chemistry of a the drug Revlimid. The floes in tutorial will cost ~$45 in Orion compute charges (the cost will vary somewhat depending on current AWS pricing).

This tutorial uses the following Floes:

Create a Tutorial Project and Working Directory

Note

If you have already created a Tutorial project while doing another tutorial you can re-use the existing one and skip this step.

  1. Log into Orion

  2. Click the Home button at the top of the left menubar.

  3. Click on the ‘Create New Project’ button and in the pop up dialog enter Tutorial for the name of the project and click ‘Save’.

Create a Dataset with Revlimid

  1. Click the Data button at the top of the left menubar.

  2. In the ‘+Add Data’ drop down menu select Sketch

  3. Paste the SMILES C1CC(=O)NC(=O)C1N2CC3=C(C2=O)C=CC=C3N into the sketching window.

  4. Enter Revlimid as the molecule title.

  5. Click the ‘Save’ button.

A new menu will pop up asking for the name of the new dataset and where to place it.

  1. Set the name of the dataset to Revlimid

  2. Set ‘Dataset will be saved in’ to Tutorial/My Data/Input Data (you may have to create the Input Data folder)

  3. Click the ‘Save’ button.

Note

You can skip this step if you have already created the ‘Revlimid’ dataset.

Run the FastROCS Plus Floe

Locate the FastROCS Plus floe as follows.

  1. Click on the ‘Floes’ button in the left menu bar

  2. Click on the ‘Floes’ tab

  3. Click ‘All Floes’ in the left pane

  4. In the search bar at the top of the right pane enter FastROCS Plus.

The FastROCS Plus floe will be visible to the right. Click on the first FastROCS Plus floe to to bring up the Job Form and set the following parameters

  • Jobs Properties

    • Output Folder : Tutorial/My Data/Revlimid FastROCS

  • Promoted Parameters

    • Inputs

      • Input Query Dataset(s) : Select the ‘Revlimid’ dataset in the Tutorial/My Data/Input Data folder.

      • FastROCS Input Collection : Select the following two datasets in the Organization Data/OpenEye Data/FastROCS Collections folder.

        • FastROCS Enamine REAL 2020q3-4 Simple 1.20B OEv1.0 - external

        • FastROCS Enamine REAL 2020q3-4 Complex 2.43B OEv1.0 - external

    • Options

      • Hit List Size : 1000

Now click the ‘Start Job’ button at the to start the FastROCS Plus job. The job will take roughly 30min to run and incur an Orion compute charge of about $40. Once the floe has finished move on to the next step of the tutorial below.

Compute Freeform Delta G of the Hit List Molecules

Locate the FreeForm Pose floe as follows.

  1. Click on the ‘Floes’ button in the left menu bar

  2. Click on the ‘Floes’ tab in the upper left of the main window.

  3. Set the ‘Browse Workfloes’ drop down menu to ‘Show all packages’

  4. Select ‘All’ under Browse Workfloes

  5. In the search bar enter Freeform Pose

  6. Click on FreeForm Pose in the list of floes to the right.

The launch interface for the FreeForm Pose will pop up. Specify the following parameters.

  • Jobs Properties

    • Output Folder : Tutorial/My Data/Revlimid FastROCS

  • Promoted Parameters

    • Inputs

      • Input Dataset : Tutorial/My Data/Revlimid FastROCS/ROCS Hit List.

      1. Click the ‘Choose Input’ button for Input Folder to open the Select Dataset modal.

      2. Click the ‘Input Data’ folder.

      3. Select the ROCS Hit List dataset

      4. Click ‘Use dataset as Input’

    • Outputs

      • Output Dataset : ROCS Hit List with FreeForm

Now click the ‘Start Job’ button at the to start the FreeForm Pose job. The job will take roughly 45min to run and incur an Orion compute charge of about $5. Once the floe has finished move on to the next step of the tutorial below.

View hit list results

Setup Basic View

Make the final hit list active and view it in the 3D window as follows

  1. Click on the ‘Data’ button in the menu

  2. Select the ‘Project Data->My Data’ folder in the list of folders to the left (this may already be selected)

  3. Main view click on the ‘Revlimid FastROCS’

  4. In the ‘Show’ menu in the top of the screen make sure ‘Datasets’ are checked.

  5. Clear any currently active datasets by opening the ‘Active Datasets’ drop down un the upper left and clicking ‘Clear All’

  6. Make the ROCS Hit List with FreeForm active by clicking on the + symbol to the left of the name to make it green.

  7. Click on ‘3D’ in the left menu bar

  8. In the Tree view highlight the ‘QM’ tag by clicking on it.

The 3D view will now open and the top scoring molecule will be visible in the 3D window along with the query molecule it has been overlayed onto. Use the up/down arrows or mouse to view different top scoring molecules overlayed onto the query.

Note

Because we gave the FastROCS Plus floe a 2D query (i.e., a molecule graph without 3D coordinates) the floe automatically generated several 3D conformers of the query and used all of them in the search and for each database molecule retained the result with the best overlay. Thus as you cycle through overlayed molecule you will see that the conformation of the query molecule may change.

View only molecule with a Freeform Delta G less than 3kcal/mol

To filter the results by freeform delta G do the following

  1. Click the ‘Filters’ button in the upper left to open the filtering down menu.

  2. Clear any existing filter by clicking on the x to the right of each existing filter in the opened drop down menu

  3. Select the ‘Freeform Pose Delta G’ from the drop down menu

  4. Set 3 as the max value for the ‘Freeform Pose Delta G’

The 3D window will now only show molecules that have a FreeForm Delta G of 3 or less.