Identification of inhibitors of biological interactions involving intrinsically disordered proteins

Int J Mol Sci. 2015 Apr 2;16(4):7394-412. doi: 10.3390/ijms16047394.

Abstract

Protein-protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs) are involved in cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few "hot spots", thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs.

Publication types

  • Review

MeSH terms

  • DNA-Binding Proteins / chemistry
  • Drug Discovery / methods
  • Humans
  • Intrinsically Disordered Proteins / chemistry*
  • Pharmaceutical Preparations / chemistry*
  • Protein Binding / drug effects

Substances

  • DNA-Binding Proteins
  • Intrinsically Disordered Proteins
  • Pharmaceutical Preparations