Defining the Binding pocket. We retrieved fasta sequences of those SLC6 targets with IC50 data points i n ChEMBL33 and imported them into Molecular Operation Environment software (MOE) (version 2020.09) . Consequently, the co-crystallized structure of the human serotonin transporter with S-citalopram (PDB ID: 5i73) was imported and all sequences were aligned in the sequence editor. Afterwards, residues within a 5 Å radius around S-citalopram were chosen, amounting to 20 residues. These 20 residues in hSERT and their corresponding residues in all SLC6 members were considered to represent the binding pockets and all remaining residues were deleted. The residue position corresponding to Y176 in hSERT was identified to be conserved in all SLC6 members and was removed from the binding pocket since it remains constant across all SLC6 members. In addition, the residue positions corresponding to A96, S336, and L337 in hSERT were identified to be involved in backbone interactions with inhibitors of SLC6 members and subsequently eliminated from the binding pocket since backbone interactions are independent of the physiochemical properties of their corresponding side chains for which descriptors are calculated. This resulted in a binding pocket of 16 residues (Figure ). Further analysis showed that the binding pockets of a given SLC6 member across different organisms were identical. This was the case for all SLC6 members except for the betaine transporter (BGT1), having Val400 in the human isoform, hBGT1, and a corresponding Met400 in the mouse isoform, mBGT1. To avoid duplicating sequences, we deleted duplicates and labeled the remaining targets in an organism-agnostic fashion. For instance, we used SERT as the label for the serotonin transporter across organisms instead of hSERT, mSERT, and rSERT for Homo sapiens, Rattus norvegicus, and Mus musculus, respectively. This required further curation steps of the dataset to prevent having identical data points with different endpoint labels, which is explained in detail in the dataset curation section.