An integrative network-based approach for drug target indication expansion

PLoS One. 2021 Jul 9;16(7):e0253614. doi: 10.1371/journal.pone.0253614. eCollection 2021.

Abstract

Background: The identification of a target-indication pair is regarded as the first step in a traditional drug discovery and development process. Significant investment and attrition occur during discovery and development before a molecule is shown to be safe and efficacious for the selected indication and becomes an approved drug. Many drug targets are functionally pleiotropic and might be good targets for multiple indications. Methodologies that leverage years of scientific contributions on drug targets to allow systematic evaluation of other indication opportunities are critical for both patients and drug discovery and development scientists.

Methods: We introduced a network-based approach to systematically screen and prioritize disease indications for drug targets. The approach fundamentally integrates disease genomics data and protein interaction network. Further, the methodology allows for indication identification by leveraging state-of-art network algorithms to generate and compare the target and disease subnetworks.

Results: We first evaluated the performance of our method on recovering FDA approved indications for 15 randomly selected drug targets. The results showed superior performance when compared with other state-of-art approaches. Using this approach, we predicted novel indications supported by literature evidence for several highly pursued drug targets such as IL12/IL23 combination.

Conclusions: Our results demonstrated a potential global approach for indication expansion strategies. The proposed methodology enables rapid and systematic evaluation of both individual and combined drug targets for novel indications. Additionally, this approach provides novel insights on expanding the role of genes and pathways for developing therapeutic intervention strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Drug Discovery / methods*
  • Humans
  • Molecular Targeted Therapy / methods
  • Protein Interaction Mapping
  • Protein Interaction Maps / drug effects*

Grant support

I confirm the commercial affiliation to Sanofi provided support in the form of salaries for authors YNH, CW, KK, DR, CZ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.