In the past, medicinal chemists also used scaffold hopping in lead structure modification. Many blockbuster drugs resulted from simple or sophisticated scaffold hops, among them various receptor ligands, e.g. β-blockers and CNS-active agents, but also drugs like atorvastatin. Even nature "used" scaffold hops, e.g. in the "design" of different β-lactame antibiotics. A very first computer program for scaffold hopping was Paul Bartlett's CAVEAT, which supports a straightforward design of peptidomimetics. The program stores bond vectors and searches for new molecular frames which are capable to bear these bonds in the very same geometry but without consideration of pharmacophore properties of the new scaffolds. TOPAS is a Roche in-house program for a RECAP-based fragmentation of molecules and their re-assembly from similar scaffolds and similar fragments.

There are three essential requirements for successful scaffold hopping: same or very similar geometry of the exit vectors of the original and the new scaffold; similar shape of the new scaffold; and compatible pharmacophore properties – otherwise no binding or different binding modes may result. By consideration of these requirements, scaffold hops turn out to be a perfect modification strategy. ReCore is a new and versatile scaffold hopping program to stimulate the creativity of the medicinal chemist, by combining three essential properties in one tool: to avoid structures with strained conformations, to enable the exploration of large search spaces, and to allow interactive use by short response times.

In conclusion, scaffold hops are a well-established strategy in lead structure optimization, especially if they are supported by appropriate software. They may result in enhanced biological activity, modulation of selectivity and/or physicochemical properties and intellectual property of "me too" analogs.