Regardless of methodological details, scaffold hopping relies on the assessment of molecular (dis)similarity, for which a variety of computational concepts have been developed . Thus, although computational scaffold hopping is an intellectually stimulating scientific exercise, interests in scaffold hopping might often be rather pragmatic in nature. In addition, the pharmaceutical industry, is also attempting to identify compounds that share activity characteristics with known candidates or drugs, but are chemically sufficiently different from them to help establish a competitive patent position.
#Molecular scaffold meaning series#
In medicinal chemistry and drug design, computational scaffold hopping aims at finding replacements of chemical liable compounds, series with flat structure–activity relationships (SARs), or (natural) molecules that are difficult to access synthetically. While benchmarking is a necessary but not sufficient exercise for evaluating virtual screening methods, prospective scaffold hopping applications starting from known active compounds are more interesting. Benchmark studies reported in the literature are often statistical in nature and do not – or not sufficiently – specify how scaffold hopping is evaluated and whether or not different structural relationships have been considered . 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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