Title:Untapped Potential of Disordered Proteins in Current Druggable Human Proteome
Volume: 17
Issue: 10
Author(s): Gang Hu, Zhonghua Wu, Kui Wang, Vladimir N. Uversky and Lukasz Kurgan
Affiliation:
Keywords:
Disorder in disorders, druggable human proteome, intrinsic disorder, intrinsically disordered proteins, human drug
target, rational drug design.
Abstract: Current efforts in design and characterization of drugs often rely on the structure of their protein targets. However,
a large fraction of proteins lack unique 3-D structures and exist as highly dynamic structural ensembles. These intrinsically
disordered proteins are involved in pathogenesis of various human diseases and are highly abundant in eukaryotes.
Based on a comprehensive analysis of the current druggable human proteome covering 12 drug classes and 18 major
classes of drug targets we show a significant bias toward high structural coverage and low abundance of intrinsic disorder.
We review reasons for this bias including widespread use of the structural information in various stages of drug development
and characterization process and difficulty with attaining structures for the intrinsically disordered proteins. We also
discuss future of intrinsically disordered proteins as drug targets. Given the overall high disorder content of the human
proteome and current bias of the druggable human proteome toward structural proteins, it is inevitable that disordered proteins
will have to raise up on the list of prospective drug targets. The protein disorder-assisted drug design can draw from
current rational drug design techniques and would also need novel approaches that no longer rely on a unique protein
structure.
