Exploring common mechanisms of adverse drug reactions and disease phenotypes through network-based analysis.
Farzaneh Firoozbakht, Maria Louise Elkjaer, Diane E Handy, Rui-Sheng Wang, Zoe Chervontseva, Matthias Rarey, Joseph Loscalzo, Jan Baumbach, Olga Tsoy
Author Information
Farzaneh Firoozbakht: Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22761 Hamburg, Germany. Electronic address: farzaneh.firoozbakht@uni-hamburg.de.
Maria Louise Elkjaer: Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22761 Hamburg, Germany.
Diane E Handy: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Rui-Sheng Wang: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Zoe Chervontseva: Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22761 Hamburg, Germany.
Matthias Rarey: ZBH - Center for Bioinformatics, University of Hamburg, Hamburg, Germany.
Joseph Loscalzo: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jan Baumbach: Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22761 Hamburg, Germany; Department of Mathematics and Computer Science, University of Southern Denmark, 5000 Odense, Denmark.
Olga Tsoy: Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22761 Hamburg, Germany.
The need for a deeper understanding of adverse drug reaction (ADR) mechanisms is vital for improving drug safety and repurposing. This study introduces Drug Adverse Reaction Mechanism Explainer (DREAMER), a network-based framework that uses a comprehensive knowledge graph to uncover molecular mechanisms underlying ADRs and disease phenotypes. By examining shared phenotypes of drugs and diseases and their effects on protein-protein interaction networks, DREAMER identifies proteins linked to ADR mechanisms. Applied to 649 ADRs, DREAMER identified molecular mechanisms for 67 ADRs, including ventricular arrhythmia and metabolic acidosis, and emphasized pathways like GABAergic signaling and coagulation proteins in personality disorders and intracranial hemorrhage. We further demonstrate the application of DREAMER in drug repurposing and propose sotalol, ranolazine, and diltiazem as candidate drugs to be repurposed for cardiac arrest. In summary, DREAMER effectively detects molecular mechanisms underlying phenotypes, emphasizing the importance of network-based analyses with integrative data for enhancing drug safety and accelerating the discovery of novel therapeutic strategies.
