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.