Strength of weakness in molecular interactions: toward transient medicines in drug discovery

Biological systems are governed by a myriad of molecular interactions, many of which remain poorly recognized. Growing evidence suggests that transient interactions (K_diss >1 µM) dominate the interactome and are crucial for dynamic molecular networks. By contrast, drug discovery has largely focused on high-affinity compounds that bind strongly to their targets. Although this strategy has delivered many successful medicines, exploiting transient interactions can offer new therapeutic opportunities, particularly for complex diseases. Transient medicines are characterized by rapid binding kinetics, concentration-driven activity and the potential for multi-target and multivalent engagement. Recognizing transient interactions as functionally important rather than biological noise could expand the drug discovery design space and establish transient medicines as a complement to current therapeutic strategies.