Drugging Fuzzy Complexes in Transcription

Transcription factors (TFs) are one of the most promising but underutilized classes of drug targets. The high degree of intrinsic disorder in both the structure and the interactions (i.e., fuzziness) of TFs is one of the most important challenges to be addressed in this context. Here, we discuss the impacts of fuzziness on transcription factor drug discovery, describing how disorder poses fundamental problems to the typical drug design, and screening approaches used for other classes of proteins such as receptors or enzymes. We then speculate on ways modern biophysical and chemical biology approaches could synergize to overcome many of these challenges by directly addressing the challenges imposed by TF disorder and fuzziness.

Automated summary

Transcription factors (TFs) are promising drug targets, but their intrinsic disorder poses challenges for drug design and screening. This study discusses the impacts of TF fuzziness on drug discovery and speculates on modern biophysical and chemical biology approaches to overcome these challenges.