Highlights

• DMPCs play a dual role by providing potent and targeted drug interactions while also posing risks of adverse drug reactions.
• Shotgun proteomics has significantly enhanced the detection and identification of low-abundance drug-metabolite-protein conjugates (DMPCs), offering better reproducibility and specificity.
• The applications of shotgun proteomics extend into drug development, enabling better understanding and utilization of DMPCs in creating effective therapeutics.

Summary

This research explores the dual roles of drug or metabolite-protein conjugates (DMPCs) in drug discovery, emphasizing both their therapeutic potential and associated risks. DMPCs arise when drugs or their metabolites bind covalently to proteins, potentially causing adverse reactions known as idiosyncratic adverse drug reactions (IADRs). However, this binding can also enhance drug efficacy and target complex diseases, making DMPCs valuable for targeting “undruggable” proteins.

The review highlights the shift towards shotgun proteomics for improved detection and analysis of DMPCs. Shotgun proteomics overcomes the limitations of traditional methods like X-ray crystallography, which require large amounts of pure protein. It offers better reproducibility and specificity, supporting drug development, toxicity investigation, and drug repurposing.

The dual nature of DMPCs is both a challenge and an opportunity in drug design. The review underscores the need for precise target identification to balance the benefits of covalent interactions against the risks, with advancements in shotgun proteomics seen as key to harnessing the potential of DMPCs in future drug discovery.

S. Gong, X. Hu, S. Chen, B. Sun, J. Wu, and N. Li, “Dual roles of drug or its metabolite−protein conjugate: Cutting‐edge strategy of drug discovery using shotgun proteomics,” Medicinal Research Reviews, vol. 42, no. 4, pp. 1704–1734, Jul. 2022, doi: 10.1002/med.21889.