Trends in Biochemical Sciences综述丨大规模靶向“不可成药”蛋白的全新策略

TL;DR - A Trends in Biochemical Sciences perspective proposes large-scale chemoproteomics on native cellular proteins to discover ligands for conventionally “undruggable” targets. Combining proteome-wide interaction maps with AI could expand drug discovery beyond proteins accessible to structure-based methods.

• Fewer than 12% of proteins are targeted by approved drugs, while only about 35% of the human proteome has experimentally resolved structures.
• Cellular assays preserve post-translational modifications, protein interactions, oligomers, aggregates, and condensates that can reshape ligand-binding opportunities.
• AI could denoise ligand–protein matrices, identify binding fingerprints, and predict unmeasured interactions or binding regions.
• Key limitations include assay bias, scarce high-quality labeled data, nonspecific binding, and the need for functional and structural validation.