A Benchmark Set of Bioactive Molecules for Diversity Analysis of Compound Libraries and Combinatorial Chemical Spaces

Sources for commercially available compounds have been
experiencing
continuous growth for several years, reaching their peak in billion-
to trillion-sized combinatorial Chemical Spaces. To assess the quality
of a compound collection to provide relevant chemistry, a benchmark
set of pharmaceutically relevant structures is required that enables
an unbiased comparison. For this purpose, the ChEMBL database was
mined for molecules displaying biological activity, and three benchmark
sets of successive orders of magnitude were created by systematic
filtering and processing: Set L (“large-sized,”
379k), Set M (“medium-sized,” 25k),
and Set S (“small-sized,” 3k). Tailored
for broad coverage of the physicochemical and topological landscape,
the benchmark Set S was then employed to analyze
the chemical diversity capacities of commercial combinatorial Chemical
Spaces and enumerated compound libraries. Among the three utilized
search methodsFTrees (pharmacophore features), SpaceLight
(molecular fingerprints), and SpaceMACS (maximum common substructure)eXplore
and REAL Space consistently performed best. In general, each Chemical
Space was able to provide a larger number of compounds more similar
to the respective query molecule than the enumerated libraries, while
also individually offering unique scaffolds for each method.