Background: Australia’s drug discovery pipeline needs to build upon current drug target identification to advance promising biomedical discoveries. Many clinically promising drugs fail due to poor efficacy, often as a result of overlooked or unclear drug mechanism of action. Recent omics approaches provide an unbiased, efficient method for identifying drug targets and biomarkers, essential for deconvoluting drug mechanisms alongside clinical development.
Objective: To develop and apply omics approaches for drug target identification and validation.
Methods and Results: We have developed and applied various proteomics and metabolomics methods for drug target identification and employed the Orbitrap Astral MS for advanced data acquisition. Specifically, for proteomics target deconvolution assays, we have established: (1) Solvent-Induced Proteome Profiling: Used MS-based proteomics to identify molecular targets by detecting drug-induced stabilization of target proteins. (2) Limited Proteolysis Mass Spectrometry: Identified drug-protein interactions by observing differential proteolysis in the proteome. (3) Chemoproteomics: Detected drug-protein binding by immobilizing test compounds and enriching binding proteins. (4) Proteolysis Targeting Chimeras (PROTACs): Employed bifunctional molecules to recruit E3 ubiquitin ligases for target protein degradation, detectable via proteomics. (5) Proximity-Based Compound-Binding Protein Identification (PROCID): Used proximity labelling with the HaloTag system to identify dynamic drug-binding proteins. The resulting datasets were analysed using our in-house developed Analyst Suites, facilitating rapid and comprehensive multi-omic data analysis. Newly developed tools in the Monash Analyst Suites enable collaborators to explore and generate novel biological insights. These methods, coupled with the Orbitrap Astral MS, enhance throughput, coverage, and quantification accuracy. They have successfully identified drug targets for various novel molecules.
Conclusion: We have significantly improved drug target identification through a range of omics-based approaches and advanced MS technology, supporting the development of novel drug candidates.
Keywords: Drug Target Identification, Multi-Omics, proteomics target deconvolution assays