Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry

Abstract

By analyzing the scaffold content of the CAS Registry, we attempt to characterize in a comprehensive way the structural diversity of organic chemistry. The scaffold of a molecule is taken to be its framework, defined as all its ring systems and all the linkers that connect them. Framework data from more than 24 million organic compounds is analyzed. The distribution of frameworks among compounds is found to be top-heavy, i.e., a small percentage of frameworks occur in a large percentage of compounds. When frameworks are analyzed at the graph level, an even more top-heavy distribution is found: half of the compounds can be described by only 143 framework shapes. The most significant finding is that the framework distribution conforms almost exactly to a power law. This suggests that the more often a framework has been used as the basis for a compound, the more likely it is to be used in another compound. This may be explained by the cost of synthesis: making a new derivative of a framework is probably less costly if many other derivatives are known. We believe this power law is evidence that the minimization of synthetic cost has been a key factor in shaping the known universe of organic chemistry.

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

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De novo branching cascades for structural and functional diversity in small molecules

“…Recent analyses of large data sets of synthetic compounds have indicated that a major part of them is presented by a small percentage of scaffolds and the same is true for drug molecules 65 . The redundancy in the scaffolds representing compound libraries that are used in the discovery research severely restrains the biological scope of the small molecules.…”

Decorated Macrocycles via Ring-Closing Double-Reductive Amination. Identification of an Apoptosis Inducer of Leukemic Cells That at Least Partially Antagonizes a 5-HT2 Receptor

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