Rational drug design targeting intrinsically disordered proteins

Abstract Intrinsically disordered proteins (IDPs) are proteins that perform important biological functions without well‐defined structures under physiological conditions. IDPs can form fuzzy complexes with other molecules, participate in the formation of membraneless organelles, and function as hubs in protein–protein interaction networks. The malfunction of IDPs causes major human diseases. However, drug design targeting IDPs remains challenging due to their highly dynamic structures and fuzzy interactions. Turning IDPs into druggable targets provides a great opportunity to extend the druggable target‐space for novel drug discovery. Integrative structural biology approaches that combine information derived from computational simulations, artificial intelligence/data‐driven analysis and experimental studies have been used to uncover the dynamic structures and interactions of IDPs. An increasing number of ligands that directly bind IDPs have been found either by target‐based experimental and computational screening or phenotypic screening. Along with the understanding of IDP binding with its partners, structure‐based drug design strategies, especially conformational ensemble‐based computational ligand screening and computer‐aided ligand optimization algorithms, have greatly accelerated the development of IDP ligands. It is inspiring that several IDP‐targeting small‐molecule and peptide drugs have advanced into clinical trials. However, new computational methods need to be further developed for efficiently discovering and optimizing specific and potent ligands for the vast number of IDPs. Along with the understanding of their dynamic structures and interactions, IDPs are expected to become valuable treasure of drug targets. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics