Create your first SAR Slides

Intro

This tutorial is a quickstart guide showing how to create a SAR Slide report around a query compound. We'll use a demo dataset (BI - HSD17B13 DATASET) and walk you through the steps required to generate SAR Reports, explain the results obtained, and fine tune them.

Step 1 - Dataset and compound selection

From the home page of the application, click on “SAR Slide” and select “New SAR Slide from MMPs”.

To create a new SAR Slide, select the "BI - HSD17B13 DATASET", and specify the “Main Endpoint” using the drop down menu. This menu allows you to choose among the different properties which were uploaded as molecule properties in the SDF file used to create the dataset.

In our case, we are interested in enzyme activity, therefore click on “Enzymatic HSD17B13 pIC50”.

Next, you'll need to select the reference compound around which we'll explore existing SAR. Pick compound 34 in the select box (you can type-in the value to avoid scrolling). You should reach the following state:

Click on the Generate SAR Slide button.

Step 2 - Explore SAR.

You should reach the following page, showing the main SAR Slides canvas with your query compound shown on the center, and a left panel enabling you to explore SAR and fine tune the visuals.

Loading fragment transformations

On the left pane, you can see your query molecule depicted with directionnal arrows. These arrows represent positions where at least one transformation exists within the dataset. When hovering on a fragment or an arrow, the part that has existing transformation is highlighted in green.

Hover your mouse on the difluorophenol moiety, and then click on it.

Groups of atoms on the query molecule that have identified changes in your dataset are surrounded with a colored halo. A floating bubble (we'll call these galleries) pointing to the halo shows, by default, 8 fragments arranged in a grid. Since we are in a matched molecular pair context, each fragment corresponds to a single transformation compared to your query molecule, and hence to a single molecule.

The query fragment will always be present and highlighted in stronger background color for easier identification.

Fragments (including query fragment) are ordered based on a given property (by default, the main endpoint you selected in the first step - can be changed using the Sort by option item), meaning that you see the transformations that correspond to the best possible values for the endpoint you selected.

In this quick start guide, the query fragment is at the first position, which means that for this substitution point, there is no existing transformation that improves the main activity.

Step 3 - Fine tune visualizations

Let's see what effects these transformation have on other properties of interest.

On the left panel, do the following:

• Change the Sort by option to Stability in Hepatocytes QH h%, so that fragments would be now ordered based on it.

• Select extra properties to display in each bubbles as follows:

Few things that are worth noting here:

• Our query fragment is now the last entry. It means that all other fragments that are visible in the gallery shows greater values for the Stability in Hepatocytes QH h% property.

• A limited number of fragments is displayed in each gallery, and the query fragment is always present. When a lot of transformation exist, there may be gaps between your query fragment and other fragment shown in the gallery. In this example, there is actually one molecule (see the +1 bellow) between query compound 34 and compound 27, and 8 others following your query molecule.

Cherry-pick Gallery Content

By default the application shows 8 compounds per floating bubble, 7 matched molecular pairs and the base compound. You can modify what is displayed inside the Gallery by accessing the "Gallery Settings" section. For the pink bubble, just click on "7/16 MMPs" on the top left corner of the bubble itself.

In this window, we show all fragments known to be a replacement for our query fragment within the dataset. It means that each entry here represents a dataset molecule. Fragments shown in the gallery are those selected in blue; fragment of the query is always selected and colored in yellow.

In here you can manually click on the compounds you want to show by selecting/unselecting them from the gallery.

Alternatively, you can use the slider under the histograms on the right-hand side of the screen. You can also use the "Add Substructure Filter" button on the left-hand side of the gallery to draw a substructure which will be used to filter the moieties in the gallery. For example, you can draw an fluorophenyl ring.

Press "Search" and the application with filter down only the corresponding compounds in the gallery.

The application lets you know that some of the fragments previously selected do not match the substructure filter. Go ahead and press the "Unselect All Filtered Out Fragments" text in the yellow area and then press the "Select All Filtered" button on the top right of the screen.

Once happy with the filtering, just press "Apply Changes". You will see the changes applied to the pink bubble.

Saving your SAR Report

By default, your latest SAR Report is saved as a browser session and will therefore disappear when you create a new SAR Report. You can choose to persist your analysis by clicking on the Save button at the bottom left of the application. You'll be prompted for a name and a description, and you can then proceed with saving.

Once saved, all your saved SAR Reports will be available at the following location: