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The structure–function paradigm, i.e. the concept that it is the three-dimensional structure of a protein that determines its function, has been partially modified by the discovery that a significant portion of the eukaryotic proteome is disordered and that this disorder is often functional. The presence of disorder is the origin of several issues, but the most relevant, at least from the biomedical point of view, is the difficulty of designing drugs in absence of a well-defined conformation of the target. To make the problem worse, we have to consider that often the disorder concerns proteins involved in diseases very relevant for human health, as cancer or neurodegenerative disorders. This review tries to summarize the state of the art of our knowledge on the subject and to describe the tools used to detect disorder and how drug design techniques used for well-folded proteins have been adjusted to this more challenging situation. Abbreviations:  AD: Alzheimer’s disease; CAID: Critical assessment of intrinsic protein disorder; CASP: Critical assessment of protein structure prediction; CD: circular dichroism; Cryo-EM: cryo-electron microscopy; DIBS: differential binding score; FRET: Förster resonance energy transfer; HD: Huntington’s disease; IDR: Intrinsically disordered regions; IDP: intrinsically disordered proteins; LDR: long intrinsically disordered regions; MG: Molten globule; MoRF: Molecular recognition feature; NMR: Nuclear magnetic resonance; PDB: Protein Data Bank; PD: Parkinson’s disease; POMS: polyoxometalates; SAXS: Small-angle X-ray scattering; SLiMS: short linear motifs; TFs: Transcription factors.

Intrinsic disorder and flexibility in proteins: a challenge for structural biology and drug design