Searching chemical space with the Bayesian Idea Generator.

The Pfizer Global Virtual Library (PGVL) is defined as a set compounds that could be synthesized using validated protocols and monomers. However, it is too large (10(12) compounds) to search by brute-force methods for close analogues of a given input structure. In this paper the Bayesian Idea Generator is described which is based on a novel application of Bayesian statistics to narrow down the search space to a prioritized set of existing library arrays (the default is 16). For each of these libraries the 6 closest neighbors are retrieved from the existing compound file, resulting in a screenable hypothesis of 96 compounds. Using the Bayesian models for library space, the Pfizer file of singleton compounds has been mapped to library space and is optionally searched as well. The method is >99% accurate in retrieving known library provenance from an independent test set. The compounds retrieved strike a balance between similarity and diversity resulting in frequent scaffold hops. Four examples of how the Bayesian Idea Generator has been successfully used in drug discovery are provided. The methodology of the Bayesian Idea Generator can be used for any collection of compounds containing distinct clusters, and an example using compound vendor catalogues has been included.