Fragment Merging

Fragment Merging with SeeSAR

Fragment merging is the concept of combining two different molecules that share an overlap at a binding site with the aim to create a compound with improved properties. This example illustrates how two inhibitors of receptor interacting protein 1 (RIP1) kinase are used as starting points for the discovery of a novel connecting core between two moieties.
Two inhibitors of receptor interacting protein 1 (RIP1) kinase. PDB-IDs: 6C3E (left) with compound 1 and 7FCZ (right) with the more complex compound 2.

Visual assessment with HYDE reveals that the triazole and the connected amide of compound 2 are contributing suboptimally to the binding affinity, while the benzimidazole moiety is tolerated better (compare the green and red spheres). Given this information we decide to keep the benzimidazole moiety of compound 1 and the cyclopropylethynyl of compound 2 and look for a replacement of the benzoxapezine core.

Goal: Find Replacement for the Connecting Scaffold

In general, there may be many reasons to replace a scaffold: unfavorable physicochemical properties, unsatisfying contribution to the the compounds affinity, unnecessary chemical complexity, or intellectual property to name a few. The goal of this case study is to find a reasonable replacement for the core between the cyclopropylethynyl group and the benzylbenzimidazole moiety thus connecting the essential fragments accomodated in different binding pockets.
In this case we will merge both fragments within the Inspirator Mode in SeeSAR.

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


Congratulations! You have discovered a new scaffold and merged two compounds. You can take it from there and improve your compound further.
You can use the Molecule Editor Mode to further increase the potency of the compound by adding and exchanging groups and atoms. Redocking can give you ideas on other potential binding poses which may have even better activity. Furthermore, you can use infiniSee to search for accessible, related compounds in vast Chemical Spaces with your designed compound as a starting point.

Download SeeSAR and infiniSee and start your drug discovery project!