Lead compounds and known scaffolds are obvious candidates as a starting point for SAR analysis and reporting. However, the selection of which one to start from when dealing with large set of molecules, or a dataset you are not familiar with (patent, external datasets...), can be quite challenging.
This how-to explains how to leverage compound and scaffold suggestions to help you identify interesting starting points.
How-to articles focus on application usage. You can read more details on how suggestions work behind the scene by reading the related articles at the bottom of the page
Starting with a compound (MMP analysis)
- Open a new SAR Slide form (from scratch or add a new analysis from any existing SAR Slide). You'll end up in the following form:
The first thing to notice, because you defined the directionality of the main endpoint upon importing the dataset, are two shortcuts below the Query Structure. By clicking on any of those, you will load the best / worst compound. This way the best / worst compound will be used as a starting point. Alternatively, you can use the Browse Suggested Structures button. To do that:
- Click on Browse Suggested Structures. Note that for large dataset, the button may be available shortly after selecting the dataset (normally after 1 or 2 seconds). You will reach a new page where you'll see a list of compounds ordered by relevancy (see Compound Suggestions for more details).
- Here, you can further refine the list by focusing on compounds that show large number of potential activity cliffs. On the left hand side, expand (if not already there) the % of Potential Cliffs filter, and select only those that have more than 70% of transformation that may be activity cliffs:
Obviously, you can also focus on compounds with potential bioisoteric transformations. To focus on bioisosteric transformations, narrow the selection to compounds with low potential activity cliff percentages.
N.B. This descriptor is based upon the threshold that you defined for the main endpoint. Different thresholds will result in different values for the descriptor.
- Once filtered, to select a compound click on the molecular structure itself. You'll be back to the initial form with the selected compound now displayed. You can now proceed to generate the SAR Slides and enhance your SAR knowledge.
Starting a scaffold (R-Group Decomposition)
Selecting a starting scaffold is composed by very similar actions compared to selecting a compound as a starting point. In the form:
- Click on the Scaffold (RGD) tab on the top of the form:
Our scaffold detection algorithm runs in parallel of the dataset import process. It is sometimes possible that the dataset import finishes before the scaffold detection process. In such case, the button will be disabled, and a tooltip will inform you on the status of the job. Just give it time to finish, after that the button will be automatically re-enabled.
Now you can directly draw your scaffold in the sketcher. Alternatively, if you to choose among different scaffolds that are suggested to you, please:
- Click on Browse Suggested Scaffolds button. You'll reach out a page showing a gallery of scaffolds (limited to 200 scaffolds max). An estimate of how many matching dataset molecules per each scaffold is shown below each box. Various scaffold properties and descriptors are also available for filtering. See Scaffold Detection for more details.
- Let's drill down to scaffolds having a maximum of 3 R-Groups by setting the R-Group Counts filter on the left filter panel:
- Now, select the scaffold of your choice by clicking on it. The scaffold will be automatically loaded in the sketcher and you shall be ready to proceed.
Happy SAR study !