Theoretical and Computational Chemistry

A close-up look at the chemical space of commercially available building blocks for medicinal chemistry



The ability to efficiently synthesize desired compounds can be a limiting factor for chemical space exploration in drug discovery. This ability is conditioned not only by the existence of well-studied synthetic protocols but also by the availability of corresponding reagents, so-called building blocks (BB). In this work, we present a detailed analysis of the chemical space of 400K purchasable BB. The chemical space was defined by corresponding synthons – fragments contributed to the final molecules upon reaction. They allow an analysis of BB physicochemical properties and diversity, unbiased by the leaving and protective groups in actual reagents. The main classes of BB were analyzed in terms of their availability, rule-of-two-defined quality, and diversity. Available BBs were eventually compared to a reference set of biologically relevant synthons derived from ChEMBL fragmentation, in order to illustrate how well they cover the actual medicinal chemistry needs. This was performed on a newly constructed universal generative topographic map of synthon chemical space, allowing to visualize both libraries and analyze their overlapping and library-specific regions.


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