Identifying Compound-Target Associations by Combining Bioactivity Profile Similarity Search and Public Databases Mining

[Image: see text] Molecular target identification is of central importance to drug discovery. Here, we developed a computational approach, named bioactivity profile similarity search (BASS), for associating targets to small molecules by using the known target annotations of related compounds from public databases. To evaluate BASS, a bioactivity profile database was constructed using 4296 compounds that were commonly tested in the US National Cancer Institute 60 human tumor cell line anticancer drug screen (NCI-60). Each compound was used as a query to search against the entire bioactivity profile database, and reference compounds with similar bioactivity profiles above a threshold of 0.75 were considered as neighbor compounds of the query. Potential targets were subsequently linked to the identified neighbor compounds by using the known targets of the query compound. About 45% of the predicted compound-target associations were successfully verified retrospectively, suggesting the possible application of BASS in identifying the targets of uncharacterized compounds and thus providing insight into the study of promiscuity and polypharmacology. Furthermore, BASS identified a significant fraction of structurally diverse compounds with similar bioactivities, indicating its feasibility of “scaffold hopping” in searching novel molecules against the target of interest.