Perform Positional Analogue Scanning using the SMILES Manager Element

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Hello,

In this tutorial, I will show you how to run a simple but powerful technique, called positional analogue scanning, in order to generate new analogs of your molecules directly in SAMSON using the SMILES Manager element. This new functionality was inspired by this blog post from Pat Walters and this paper from Lewis Pennington, Ingo Muegge, and coworkers. It will allow you to evaluate the effects of newly introduced changes of your molecules on their properties, like the binding affinity (using Autodock Vina Extended SAMSON element) or by looking at their key interactions with a target protein directly in SAMSON. For the purpose of this tutorial, let’s consider the case presented in the previously cited paper with the corresponding SMILES code: CN1C=C(C(=O)Nc2ccc(-c3ccccc3)c(c2)C(F)(F)F)C(=O)c2ccccc12

Start from a single molecule

Let’s begin by defining our starting molecule. You can do that in two different ways: either you enter the SMILES code of your molecule of interest or you select it in the SAMSON document and you press on the Use selection button like in the gif below.

 

Define your searched pattern

Search in the initial structure the pattern you want to replace or to which you want to attach new a atom or group. In our example, we will use aromatic carbon as a pattern by entering the SMARTS code [cH] in the corresponding field. Like shown in the following gif, we can see that the found pattern in the initial molecule was highlighted a number of times.

Replace or attach

Now that we specified the pattern we want to scan, we choose the first option in order to replace it with a nitrogen atom (N). If you like, you can choose to attach to your pattern a fluorine atom (F) or a methyl group (CH3). Then we only have to click on run to generate the analogs and display them in the results section of the interface.

As you can see, it was quite fast to generate the SMILES codes and the 2D depiction of the analogs.

Modify your results

In the results table you can do many actions:

  • Modify the generated analogs: change the name or the SMILES code of the analogue of your choice by double clicking on the corresponding cell in the results table.
  • Open the 2D depiction image: double click on the 2D depiction image to open it in a bigger window. You can also do that by right clicking on the image and clicking on open in the context menu.
  • Hide/show the analogs’ images in the results table: click on the 2D cell of the table’s header to hide or show the 2D images in the results table.
  • Generate 3D structure of a specific analogue: right-click on the image of your analogue of interest and choose generate 3D structure in the opened context menu.
  • Remove only selected results: select the lines of the analogs you want to remove from the results table and click on Remove selected results button.
  • Clear results table content: click on the Clear results button to remove all the generated analogs from the table.

Generate 3D structures of your analogs and study them

Finally, lets generate the 3D structures of our generated analogs by clicking on the Convert to 3D button.

Now, you can proceed in the study of your molecules, for example, by performing a docking of the generated analogs using the Autodock Vina Extended element. You can then examine which changes preserve key interactions with your target protein and which ones make new interactions.

Don’t hesitate to give us your feedback on this new feature either on the forum or by reaching out to us by email.

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