Scaffolds extracted from bioactive compounds represent a wide spectrum of structural relationships, ranging from chemically very similar scaffolds to others that are structurally unrelated. For benchmarking of virtual screening methods, the assessment of scaffold hopping potential has become a gold standard, which is not without problems. Core structure modifications or replacements might be attempted on the basis of chemical knowledge, at least for individual compound series, but searching for scaffold hops requires computational frameworks. Thus, the goal of scaffold hopping is the identification of structurally diverse compounds that are similar in activity/property space . Besides activity, other molecular properties might also be considered. It refers to the search for compounds that have similar activity but contain different core structures.
The ‘scaffold hopping’ concept originated from computational chemistry and virtual compound screening . However, for systematic computational analysis of scaffolds, the consistent application of a formal definition is essential . Preferences for scaffold definitions may vary. This approach extracts scaffolds from analog series, rather than individual compounds, and takes reaction information into account . Recently, an alternative scaffold methodology has been introduced to further increase the medicinal chemistry relevance of computationally generated scaffolds . It follows that each ring-containing compound yields a scaffold and that the addition of a ring to a compound (which may be regarded as an R-group) always generates a new scaffold. On the basis of this definition, scaffolds are obtained from compounds by removal of substituents (R-groups) while retaining ring systems and linker fragments between rings . In computational analysis, a hierarchical definition of scaffolds has dominated the field for two decades . Scaffolds might be defined algorithmically or on the basis of medicinal chemistry knowledge . The ‘scaffold’ concept is widely applied in medicinal chemistry and drug design to generate, analyze, and compare core structures of active compounds and analog series .
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