Figure 1

Schematic of computational chemoproteomics pipeline to identify psychoactives for mental-health indications using the CANDO platform. The version (v1) of the CANDO platform used in this study evaluated interactions between 3,733 human ingestible compounds (including the 428 psychoactives listed in Tables S1–S6) that are associated with 2030 indications (including 137 related to mental health and epilepsy disorders) and 48,278 protein structures (46,784 used to compute the structural interactome). The chemoproteomics interaction signatures are ranked according to the degree of interaction and similarity for all indications. The signature comparison (RMSD) and ranking approach (TopX predictions) yielded benchmarking accuracies of 12–25% for 1439 indications with at least two approved compounds. 58/163 (35%) top ranking predictions had comparable or better activity relative to existing drugs in twelve prospective in vitro studies across ten indications. We expect these findings to hold for evaluating the potential of psychoactives in treating mental health indications, which we then analysed holistically to determine global patterns and make predictions of putative drug leads for these indications.