On Scaffolds and Hopping in Medicinal Chemistry

Abstract

The molecular scaffold is an oft-cited concept in medicinal chemistry suggesting that the definition of what makes a scaffold is rigorous and objective. However, this is far from the case with the definition of a scaffold being highly dependent on the particular viewpoint of a given scientist. It follows, therefore, that the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. These techniques are adapted from chemoinformatics to be applied in the design of new medicinal compounds.

Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics

“…Using scaffold hopping, 18 we designed several alterations of the core framework of compound 1 (data not shown) that permit a similar geometric arrangement of the side chains (regions A and C, Figure 1). Among the scaffolds generated from this exercise, the benzothiazole-based scaffold 2 ( Figure 1) emerged as a potential lead for a core structure.…”

Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

“…Bioisostere searching involves swapping functional groups of a molecule with other functional groups that have similar biological properties. Scaffold hopping is an approach to discover structurally novel compounds starting from known active compounds by modifying the central core structure of the molecule (Brown and Jacoby, 2006). Scaffold hopping is an important drug design strategy to develop novel molecules with potent activity, altered physicochemical attributes, and Absorption, Distribution, Metabolism, Excretion and Toxicity -ADMET-properties.…”

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].…”