Discovery of disease treatment mechanisms through the multiscale interactome

Most diseases disrupt multiple genes, and drugs treat such diseases by restoring the functions of the disrupted genes. How drugs restore these functions, however, is often unknown as a drug9s therapeutic effects are not limited only to the genes that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach for the discovery of disease treatment mechanisms. We integrate disease-perturbed genes, protein targets, and functional pathways into a multiscale interactome network, which contains 478,728 interactions between 1,661 drugs, 840 diseases, 17,660 proteins, and 9,798 functional pathways. We find that a drug9s effectiveness can often be attributed to targeting genes that are distinct from disease-associated genes but that affect the same functional pathways. We develop a random walk-based method that captures how drug effects propagate through functional pathways in a multiscale manner and are coordinated by the protein-protein interaction network in which drugs act. On three key pharmacological tasks, we find that the multiscale interactome predicts what drugs will treat a given disease up to 40% better than prior approaches, reveals treatment mechanisms, and has the unique ability to explain how genetic mutations interfere with treatment mechanisms to cause drug resistance and serious adverse reactions. Our results indicate that molecular-scale interactomes (i.e., protein-protein interaction networks) alone are unable to explain the therapeutic effects of drugs as many drugs treat diseases by reinstating the functional pathways disrupted by the disease rather than directly targeting disease …