Druggability of Intrinsically Disordered Proteins

Abstract

Although the proteins in all the current major classes considered to be druggable are folded in their native states, intrinsically disordered proteins (IDPs) are becoming attractive candidates for therapeutic intervention by small drug-like molecules. IDPs are challenging targets because they exist as ensembles of structures, thereby making them unsuitable for standard rational drug design approaches, which require the knowledge of the three-dimensional structure of the proteins to be drugged. As we review in this chapter, several different small molecule strategies are currently under investigation to target IDPs, including: (i) to stabilise IDPs in their natively disordered states, (ii) to inhibit interactions with ordered or disordered protein partners, and (iii) to induce allosteric inhibition. In this context, biophysical techniques, including in particular nuclear magnetic resonance (NMR) spectroscopy and small-angle X-ray scattering (SAXS) coupled with molecular dynamics simulations and chemoinformatics approaches, are increasingly used to characterize the structural ensembles of IDPs and the specific interactions that they make with their binding partners. By analysing the results of recent studies, we describe the main structural features that may render IDPs druggable, and describe techniques that can be used for drug discovery programs focused on IDPs.

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…For this reason, assignation of the middle (CORE) segment of the full length TPPP/p25 by means of multinuclear NMR has failed [10]. Different strategies have been suggested for targeting these versatile IDP proteins [52,53]. A relevant strategy is "to inhibit interactions with ordered or disordered protein partners" [52].…”

“…Different strategies have been suggested for targeting these versatile IDP proteins [52,53]. A relevant strategy is "to inhibit interactions with ordered or disordered protein partners" [52]. In fact, there are only a limited number of IDP-related systems studied in drug design; the small molecule inhibitors were mostly identified by experimental screening without considering the mechanism or the toxic side effects of the inhibition [54,55].…”

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

“…These disease‐associated IDPs commonly play principal roles as hub proteins in the disease‐associated protein‐protein interaction networks that are potential drug targets. There is significant interest in exploiting the relatively unexplored potential of these proteins in drug discovery driven by the need to find new therapeutic targets . The IDPs have unique structural properties such as high flexibility and conformational plasticity, which allow them to adopt different conformations when bound to different targets.…”

“…The rational drug design is usually based on the well‐defined 3D structure of globular proteins; however, targeting disordered proteins is a challenging task, since these proteins exist in a highly flexible state and form a dynamic structural ensemble without a well‐defined 3D structure. Novel strategies and the combination of computational and experimental methods are necessary to tackle this challenge . The strategies suggested for targeting IDPs include: (a) the stabilization of the disordered states; (b) inhibition of the interactions with ordered or disordered protein partners; and (c) induction of allosteric inhibition .…”

“…Novel strategies and the combination of computational and experimental methods are necessary to tackle this challenge . The strategies suggested for targeting IDPs include: (a) the stabilization of the disordered states; (b) inhibition of the interactions with ordered or disordered protein partners; and (c) induction of allosteric inhibition . In this context, biophysical techniques, including NMR and small‐angle X‐ray scattering coupled with molecular dynamics simulations approaches, are increasingly used to characterize the homo‐ and hetero‐associations of IDPs that may lead to possible strategies to target aggregation‐prone IDPs implicated in conformational diseases .…”