In Silico Investigations into the Selectivity of Psychoactive and New Psychoactive Substances in Monoamine Transporters

New psychoactive substances (NPS) are a group of compounds that mimic the effects of illicit substances. A range of NPS have been shown to interact with the three main classes of monoamine transporters (DAT, NET, and SERT) to differing extents, but it is unclear why these differences arise. To aid in understanding the differences in affinity between the classes of monoamine transporters, several in silico experiments were conducted. Docking experiments showed there was no direct correlation between a range of scoring functions and experimental activity, but Spearman ranking analysis showed a significant correlation (α = 0.1) for DAT, with the affinity ΔG (0.42), αHB (0.40), GoldScore (0.40), and PLP (0.41) scoring functions, and for DAT (0.38) and SERT (0.40) using a consensus scoring approach. Qualitative structure–activity relationship (QSAR) experiments resulted in the generation of robust and predictive three-descriptor models for SERT (r² = 0.87, q² = 0.8, and test set r² = 0.74) and DAT (r² = 0.68, q² = 0.51, test set r² = 0.63). Both QSAR models described similar characteristics for binding, i.e., rigid hydrophobic molecules with a biogenic amine moiety, and were not sufficient to facilitate a deeper understanding of differences in affinity between the monoamine transporters. This contextualizes the observed promiscuity for NPS between the isoforms and highlights the difficulty in the design and development of compounds that are isoform-selective.