Public Domain HTS Fingerprints: Design and Evaluation of Compound Bioactivity Profiles from PubChem’s Bioassay Repository

Molecular profiling efforts aim at
characterizing the biological
actions of small molecules by screening them in hundreds of different
biochemical and/or cell-based assays. Together, these assays yield
a rich data landscape of target-based and phenotypic effects of the
tested compounds. However, submitting an entire compound library to
a molecular profiling panel can easily become cost-prohibitive. Here,
we make use of historical screening assays to create comprehensive
bioactivity profiles for more than 300 000 small molecules.
These bioactivity profiles, termed PubChem high-throughput
screening fingerprints (PubChem HTSFPs), report small molecule
activities in 243 different PubChem bioassays. Although the assays
originate from originally independently pursued drug or probe discovery
projects, we demonstrate their value as molecular signatures when
used in combination. We use these PubChem HTSFPs as molecular descriptors
in hit expansion experiments for 33 different targets and phenotypes,
showing that, on average, they lead to 27 times as many hits in a
set of 1000 chosen molecules as a random screening subset of the same
size (average ROC score: 0.82). Moreover, we demonstrate that PubChem
HTSFPs retrieve hits that are structurally diverse and distinct from
active compounds retrieved by chemical similarity-based hit expansion
methods. PubChem HTSFPs are made freely available for the chemical
biology research community.