Fig. 2. The multiscale interactome accurately predicts what drugs treat a disease and systematically identifies proteins and biological functions related to treatment.

a To predict whether a drug treats a disease, we compare the drug and disease diffusion profiles according to a correlation distance. b By incorporating both proteins and biological functions, the multiscale interactome improves predictions of what drug will treat a given disease by up to 40% over molecular-scale interactome approaches¹³. Reported values are averaged across five-fold cross validation (see the “Methods” section); multiscale interactome values are in bold. c The multiscale interactome outperforms the molecular-scale interactome most greatly on drug classes known to harness biological functions that describe processes across the body (i.e., pituitary, hypothalamic hormones and analogs). d Existing interactome approaches are black boxes: they predict what drug treats a disease but do not explain how the drug treats the disease through specific biological functions^10–15. e By contrast, the drug and disease diffusion profiles (r^(c) and r^(d)) reveal the proteins and biological functions relevant to treatment. For each drug and disease pair, we induce a subgraph on the k most frequently visited nodes in the drug and disease diffusion profiles to explain treatment. f Drugs with more similar diffusion profiles have more similar gene expression signatures (Spearman ρ = 0.392, p = 5.8 × 10⁻⁷, n = 152, two-sided), suggesting that drug diffusion profiles capture their biological effects. g The multiscale interactome explains treatments that molecular-scale interactome approaches cannot faithfully represent. Rosuvastatin treats Hyperlipoproteinemia Type III by binding to HMG CoA reductase (HMGCR) which drives a series of cholesterol biosynthetic functions affected by Hyperlipoproteinemia Type III^50–56. h Anakinra treats cryopyrin-associated periodic syndromes (CAPS) by binding to IL1R1 which regulates immune-mediated inflammation through the Interleukin-1 beta signaling pathway^30,58. Inflammation is a hallmark of CAPS⁵⁷. Abbreviations: reg. regulation, path. pathway, proc. process, cell. cellular, + positive, − negative. Boxplots: median (line); 95% CI (notches); 1st, 3rd quartiles (boxes); data within 1.5 × the inter-quartile range from the 1st, 3rd quartiles (whiskers). Sample sizes in parentheses.