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This content will become publicly available on December 1, 2022

Title: Identification of disease treatment mechanisms through the multiscale interactome
Abstract Most diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug’s therapeutic effects are not limited to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network. We then develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and physical protein-protein interactions. On three key pharmacological tasks, the multiscale interactome predicts drug-disease treatment, identifies proteins and biological functions related to treatment, and predicts genes that alter a treatment’s efficacy and adverse reactions. Our results indicate that physical interactions between proteins alone cannot explain treatment since many drugs treat diseases by affecting the biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for explaining treatment, even when drugs seem unrelated to the diseases they are recommended for.
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Award ID(s):
2030477 2030459 1835598 1934578 1918940
Publication Date:
Journal Name:
Nature Communications
Sponsoring Org:
National Science Foundation
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