Why are there no clinically-approved drugs targeting disordered proteins?

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are critical regulators in health and disease but remain underexploited as drug targets. Unlike folded proteins, they populate dynamic ensembles where interactions can be transient or multivalent, and both enthalpic and entropic contributions shape binding, complicating ligand discovery. Here, we analyze three key barriers hindering progress: (1) nontraditional binding mechanisms that challenge classical drug design, (2) experimental and computational limitations for studying disorder, and (3) a lack of systematic datasets. Our analysis of the Biological Magnetic Resonance Data Bank (BMRB) and BindingDB highlights the extreme underrepresentation of IDPs and IDRs, underscoring the need for community-driven data resources. By integrating new binding paradigms, tailored methodologies, and standardized datasets, drug discovery can begin to harness IDPs as a new therapeutic frontier.