Biophysical and Integrative Characterization of Protein Intrinsic Disorder as a Prime Target for Drug Discovery

Protein intrinsic disorder is increasingly recognized for its biological and disease-driven functions. However, it represents significant challenges for biophysical studies due to its high conformational flexibility. In addressing these challenges, we highlight the complementary and distinct capabilities of a range of experimental and computational methods and further describe integrative strategies available for combining these techniques. Integrative biophysics methods provide valuable insights into the sequence-structure-function relationship of disordered proteins, setting the stage for protein intrinsic disorder to become a promising target for drug discovery. Finally, we briefly summarize recent advances in the development of new small molecule inhibitors targeting the disordered N-terminal domains of three vital transcription factors.

Automated summary

Protein intrinsic disorder is recognized for its biological and disease-driven functions, but its high conformational flexibility presents challenges for biophysical studies. Complementary experimental and computational methods, as well as integrative strategies, provide valuable insights into the sequence-structure-function relationship of disordered proteins. Recent advances in small molecule inhibitors targeting disordered N-terminal domains of vital transcription factors are summarized.