Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm

Abstract

Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure−function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

“…Secondly, it suggests that iterative analog optimization is a feasible strategy to generate high-affinity ligands of disordered proteins, following similar paradigms well-established for structured protein targets. 41…”

High-throughput assay exploiting disorder-to-order conformational switches: application to the proteasomal Rpn10:E6AP complex

“…1. Such exploitation of a disorder-to-order transition of an intrinsically disordered protein (IDP) or region (IDR) is of therapeutic interest, [36][37][38] especially when induced by a native binding partner; for example, p27 with Cdk2/cyclin A, 39,40 MAX with cMyc, 41,42 and p53 with MDM2. [43][44][45] Thus, the approach we describe herein for Rpn10:E6AP, whereby binding is monitored by using environmentally sensitive uorophores as sensors for conformational switching, can be applied generally to other therapeutically relevant protein systems to either characterize dynamic behavior and/or to perform high-throughput (HTP) screening for therapeutic discovery.…”

Small molecules targeting the structural dynamics of AR-V7 partially disordered protein using deep learning and physics based models

“…Such conformations often lack a stable and single active binding site that can be used for in-silico screening and designing small molecules. Despite these obstacles, targeting PDPs is a critical area of research due to their significant role in various biological processes 6 and their link to a multitude of human diseases, such as cancer 2 , neurodegenerative diseases 3 and many others 6 . Previous analyses of the structures of 51 intrinsically disordered proteins (IDPs), which are PDPs that have no stable secondary structure fold at all, revealed that on average, PDPs contain 50% more druggable pockets than fully structured proteins.…”

“…The process of discovering new drugs is both expensive and time-consuming, facing several hurdles including the challenge of finding at the preclinical level effective drug candidates through high-throughput screening methods, which often have low success rates 1,2 . To tackle these issues, the use of computer-aided drug discovery (CADD) has become increasingly important.…”