Beyond Known Drug Targets: Uncovering Hidden Molecular Risks of Polypharmacy

Linköping University, Sweden | Chemical–protein interactions and thermal proteome profiling

Our research group at Linköping University investigates chemical–protein interactions and molecular mechanisms of toxicity using mass spectrometry-based proteomics and complementary biochemical approaches. Our published work demonstrates proteome-wide target identification and the prioritisation of candidate molecular initiating events for toxicity pathways.

We propose to investigate the molecular effects of multiple medications as mixtures of bioactive compounds, identifying unexpected protein interactions and exploring how these effects may contribute to differences in adverse drug reaction (ADR) susceptibility across patient groups.

Proposed scientific contributions and outputs:

• Discovery of unexpected protein interactions: Apply proteome integral solubility alteration (PISA) profiling to investigate protein perturbations associated with clinically relevant drug combinations, including effects not anticipated from known therapeutic targets.

• Identification of potentially adverse mechanisms: Integrate proteome-wide target findings with pathway analysis and molecular initiating event prioritisation to identify biological processes potentially affected by multidrug exposure.

• Mechanistic assessment of patient-group susceptibility: Compare drug-associated molecular perturbations with disease-related pathways and clinical characteristics to investigate potential vulnerabilities in defined patient groups.

• Evaluation of functional and predictive relevance: Test prioritised molecular effects and assess, with consortium partners, whether mechanistic information adds value to existing approaches for ADR risk stratification.

Expected added value to the consortium: A complementary approach to understanding polypharmacy that reveals unexpected molecular effects of drug combinations and provides experimentally supported mechanistic information for evaluating ADR susceptibility and patient stratification.

We are seeking a coordinator developing a consortium for HORIZON-HLTH-2027-01-CARE-02. We offer expertise in proteome-wide chemical–protein interaction analysis, mechanistic toxicology and molecular pathway interpretation, complementing clinical pharmacology, pharmacogenomics, patient stratification and predictive modelling.