Targeting intrinsically disordered proteins at the edge of chaos

Intrinsically disordered proteins or intrinsically disordered regions (IDPs or IDRs) are those that do not fold into defined tertiary structures under physiological conditions. Given their prevalence in various diseases, IDPs are attractive therapeutic targets. However, because of the dynamic nature of the IDP structure, conventional structure-based drug design methods cannot be directly applied. Thanks to recent progress in understanding the mechanisms underlying IDP and ligand interactions, computational strategies for IDP-targeted rational drug discovery are emerging. Here, we summarize recent developments in computational IDP drug design strategies and their successful applications, analyze the typical properties of reported IDP-binding compounds (iIDPs), and discuss the major challenges ahead as well as possible solutions.