SynthI: A New Open-Source Tool for Synthon-Based Library Design.

Most of the existing computational tools for de novo library design are focused on the generation, rational selection, and combination of promising structural motifs to form members of the new library. However, the absence of a direct link between the chemical space of the retrosynthetically generated fragments and the pool of available reagents makes such approaches appear as rather theoretical and reality-disconnected. In this context, here we present Synthons Interpreter (SynthI), a new open-source toolkit for de novo library design that allows merging those two chemical spaces into a single synthons space. Here synthons are defined as actual fragments with valid valences and special labels, specifying the position and the nature of reactive centers. They can be issued from either the "breakup" of reference compounds according to 38 retrosynthetic rules or real reagents, after leaving group withdrawal or transformation. Such an approach not only enables the design of synthetically accessible libraries and analog generation but also facilitates reagents (building blocks) analysis in the medicinal chemistry context. SynthI code is publicly available at https://github.com/Laboratoire-de-Chemoinformatique/SynthI.

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 (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 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 BBs 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 that enables visualization of both libraries and analysis of their overlapped and library-specific regions.