Fragment Growing

Fragment Growing with SeeSAR

Fragment growing is the addition of molecular decorations on a small molecule. Fragments are small molecule binders with low molecular weight and binding affinity. Yet, if they bind, they display high quality interactions with the target structure, making them perfect starting points for compound evolution. This example illustrates how to grow a fragment binder of VIM-2 MBL to increase the affinity of the compound.

Goal: Find Complementary Fragment Decorations

In general, fragment binders bind only in a small cavity leaving the rest of the available space unoccupied. This presents a good opportunity to attach or replace groups to the molecule to introduce additional interaction partners for the binding with the structure thus increase the affinity. Those decorations can be in-house or commercial building blocks facilitating straight-forward synthesis of lead compounds.
The goal of this study is to grow into an unoccupied binding pocket to improve the compound. It is worthwile to mention that the increase of binding affinity is only one aspect of fragment growing. Furthermore, it can be used to add groups to fill binding subpockets that are only present in the target of interest but not in other structures binding the compound to improve the selectivity.

Continue this tutorial in SeeSAR and the step-by-step guide. Please use the attached PDB files.


Congratulations! You have discovered several decorations for the fragment.
Why stop there? Use the acquired knowledge to grow into the second binding pocket to further increase the affinity of the compound.
You can also become creative yourself and add groups to your fragment in the Molecule Editor Mode and play around to see what works and what does not. This can help you to get some ideas where lipophilic moieties may be necessary or where you can add a hydrogen bond acceptor/donor to increase the affinity of your compound.

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