Scaffold hopping

Abstract

The aim of scaffold hopping is to discover structurally novel compounds starting from known active compounds by modifying the central core structure of the molecule. Scaffold hopping is a central task of modern medicinal chemistry requiring a multitude of techniques, which are discussed in this article. Their application has led to several molecules with chemically completely different core structures, and yet binding to the same receptor. Computational approaches for scaffold hopping highlight the challenges of the field that are still unsolved.:

Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A

“…2b, yellow and orange wires) have been analyzed by Meijere et al 14,15 These analyses importantly demonstrates that no hydrogen bond is 2 | J. Name., 2012, 00, [1][2][3] This journal is © The Royal Society of Chemistry 2012…”

“…1,2 The introduction and/or modification of substituents of a lead are commonly investigated to optimize these properties, but, a more drastic structural change, i.e., scaffold hopping, is occasionally needed to identify drug candidates with the desired properties. [3][4][5][6][7] Although natural products are useful sources of drug candidates, their complex structures sometimes limit their use as clinical drugs. 8 Peptides are also potentially useful for the treatment of diseases, but their low membrane permeability and biological stability often limit their application as clinical drugs.…”

Analysis and use of fragment-occurrence data in similarity-based virtual screening

“…We also noted the numbers of distinct Murcko scaffolds in the active molecules that were retrieved, rather than just the number of active molecules. As recommended by Good et al [33], this was done to assess the effectiveness of the various weighting schemes for scaffold-hopping [41][42][43].…”

Identification of target-specific bioisosteric fragments from ligand–protein crystallographic data

“…The use of bioisosterism to support lead optimisation will also be the focus of the work reported here. It is, however, worth noting that there is now also increasing interest in the use of scaffold-hopping techniques to suggest replacement ring systems that can locate functionality at the appropriate locations in 3D space whilst providing a novel patent position (see, e.g., [7][8][9]). …”