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 wellstudied synthetic protocols but also by the availability of corresponding reagents, so-called building blocks (BBs). In this work, we present a detailed analysis of the chemical space of 400 000 purchasable BBs. The chemical space was defined by corresponding synthonsfragments 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 BBs were analyzed in terms of their availability, rule-oftwo-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 that enables visualization of both libraries and analysis of their overlapped and library-specific regions.

Automated summary

Efficient synthesis of desired compounds is crucial for chemical space exploration in drug discovery, which is influenced by both established synthetic protocols and the availability of corresponding building blocks (BBs). This study analyzes the chemical space of 400,000 purchasable BBs, examining their physicochemical properties and diversity to assess their coverage of medicinal chemistry needs. The analysis is based on a universal topographic map that visualizes libraries and their differences in coverage.