Scientists crack how protein tweaks unlock 'undruggable' drug targets

A new study has uncovered how posttranslational modifications (PTMs) reshape the way proteins bind to potential drugs. These chemical changes can create new binding sites or alter existing ones, transforming how proteins interact with therapeutic molecules. The findings suggest fresh opportunities for targeting proteins once considered 'undruggable'. PTMs modify proteins in ways that affect their activity, stability, and location within cells. The study shows these changes also dramatically shift the ligand-binding landscape of the proteome. In some cases, entirely new binding pockets form, while in others, existing ones are altered or blocked.

Researchers identified specific PTM 'hotspots'—regions where modifications consistently influence ligandability across different protein families. By mapping these changes, the team revealed how disease states might rewire protein interactions, offering clues for new biomarkers and drug targets. The dataset produced by the study provides a detailed resource for future research. It highlights how drug development could improve by factoring in PTM effects during hit identification and lead optimisation.

The study’s insights could expand the range of proteins available for drug targeting. By accounting for PTM-induced structural shifts, researchers may uncover new ways to modulate protein activity in disease. The findings also open doors for designing therapies that exploit these dynamic binding changes.