biostudies-literatureUnknown5Schottlender GStructural similarity metrics such as the Tanimoto coefficient (TC) miss many functionally related compounds-indeed, 60% of similarly bioactive ligand pairs in the ChEMBL database show TC < 0.30, revealing a major blind spot that constrains ligand-based discovery. Our motivation is to overcome this blind spot and enable the recovery of structurally different yet functionally equivalent chemotypes that structure-based similarity fails to detect. Here, we introduce the bioactivity similarity index (BSI), a machine learning model that estimates the probability that two molecules bind the same or related protein receptors. Trained under leave-one-protein-out (LOPO) across Pfam-defined protein groups on dissimilar pairs, BSI not only outperforms TC but also surpasses modern molecular embedding Frontiers in bioinformatics1695353https://www.ebi.ac.uk/biostudies/studies/S-EPMC12698616biostudies-literatureBeyond Tanimoto: a learned bioactivity similarity index enhances ligand discovery.PMC12698616Marti MASchottlender GFernandez Do Porto DPrieto JMfalseBeyond Tanimoto: a learned bioactivity similarity index enhances ligand discovery.Structural similarity metrics such as the Tanimoto coefficient (TC) miss many functionally related compounds-indeed, 60% of similarly bioactive ligand pairs in the ChEMBL database show TC < 0.30, revealing a major blind spot that constrains ligand-based discovery. Our motivation is to overcome this blind spot and enable the recovery of structurally different yet functionally equivalent chemotypes that structure-based similarity fails to detect. Here, we introduce the bioactivity similarity index (BSI), a machine learning model that estimates the probability that two molecules bind the same or related protein receptors. Trained under leave-one-protein-out (LOPO) across Pfam-defined protein groups on dissimilar pairs, BSI not only outperforms TC but also surpasses modern molecular embedding 2025-01-01T00:00:00Z20252026-05-26T17:07:41.868Z2026-05-25T03:07:47.554ZS-EPMC126986164139379110.3389/fbinf.2025.1695353