Scaffold-based similarity

Scaffold-based similarity is very intuitive for chemists. Molecules with a small overall similarity (e. g., based on their Tanimoto coefficients) are grouped together 

On the other hand, the pharmacophore of a molecule is often defined by the arrangement of functional groups and not by the scaffold. For this reason, there may be a discrepancy between similarity from the point of view of the chemist and similarity as seen by a biologist [64, 65]. 

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Renner, S. and Schneider, G. (2006) Scaffold-hopping potential of ligand-based similarity concepts. ChemMedChem, 1, 181-185. 

Given the success of Bertozzi s example, it is perhaps surprising that not more multivalent scaffolds based on glycosyl hydrazide chemistry have been reported. One of the few examples has been described by Liu and coworkers, who have shown that oligosaccharides can readily be displayed on modified poly(amido amine) (PAMAM) dendrimers via a hydrazide linkage. These dendrimers were shown to be readily taken up by hepatocytes in a glycan-dependent fashion [35]. Similarly, dendrimers have been used to increase the density of carbohydrate... 

A third approach is to select a diverse set of scaffolds as opposed to picking diverse analogs within a single series. Diverse scaffolds can be chosen on the basis of 2D or 3D similarity metrics. In addition, several groups have also developed methods for evaluating the diversity of scaffolds based on the spatial placement of side chains. ... 

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