What is scaffold hopping?

The scaffold of a molecule is its core framework — the ring systems and linkers that hold the functional groups in place. Scaffold hopping means replacing that core with a different one while keeping the groups that interact with the target in roughly the same 3D positions.

Why hop?

• Intellectual property. A new core can escape a crowded patent space.
• Properties. A different scaffold may fix poor solubility, metabolic instability or toxicity linked to the original core. See ADMET.
• Synthesis. A more accessible core can make analogues cheaper and faster to produce.
• Rescue. When a series stalls, a hop opens new structure–activity relationships.

Types of scaffold hop

1. Heterocycle replacement — swapping atoms in a ring, for example a phenyl for a pyridine.
2. Ring opening or closure — adding or removing a ring to change flexibility. Closing a large ring is the route to macrocycles.
3. Peptide mimicry — replacing a peptide backbone with a non-peptide scaffold that presents the same side chains.
4. Topology-based hops — entirely new frameworks that share only the 3D arrangement of key features.

Computational support

Because a successful hop by definition looks different in 2D, standard 2D fingerprint similarity is a weak guide. Useful methods include pharmacophore and 3D shape similarity, docking of candidate replacements, and searches over libraries of 3D linkers or fragments that can bridge the groups you want to keep. The last approach is closely related to fragment linking.