Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Abstract

Protein‐protein interactions (PPIs) are closely implicated in various types of cellular activities and are thus pivotal to health and disease states. Given their fundamental roles in a wide range of biological processes, the modulation of PPIs has enormous potential in drug discovery. However, owing to the general properties of large, flat, and featureless interfaces of PPIs, previous attempts have demonstrated that the generation of therapeutic agents targeting PPI interfaces is challenging, rendering them almost “undruggable” for decades. To date, rapid progress in chemical and structural biology techniques has promoted the exploitation of allostery as a novel approach in drug discovery. By attaching to allosteric sites that are topologically and spatially distinct from PPI interfaces, allosteric modulators can achieve improved physiochemical properties. Thus, allosteric modulators may represent an alternative strategy to target intractable PPIs and have attracted intense pharmaceutical interest. In this review, we first briefly introduce the characteristics of PPIs and then present different approaches for investigating PPIs, as well as the latest methods for modulating PPIs. Importantly, we comprehensively review the recent progress in the development of allosteric modulators to inhibit or stabilize PPIs. Finally, we conclude with future perspectives on the discovery of allosteric PPI modulators, especially the application of computational methods to aid in allosteric PPI drug discovery.

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

“…Allostery involves fine-tuning the functions of conserved orthosteric sites by topologically distinct allosteric sites. Allosteric ligands exhibit higher selectivity and better physio-chemical properties than orthosteric ligands, which offers a new paradigm for innovative therapeutic development [1][2][3][4][5][6] . Allostery has enabled the successful modulation of intractable drug targets, such as oncoprotein Ras, recalcitrant kinases, and G-protein-coupled receptors (GPCRs) [5][6][7][8][9][10][11][12][13] .…”

<p>Current Challenges and Opportunities in Designing Protein–Protein Interaction Targeted Drugs</p>

“…18 Moreover, more than 800 drug development projects related to PPIs were published in PubChem in 2012. 19 The p53/Mdm2 complex is a typical example of a PPI target. P53 is a tumor suppressor protein that is strongly downregulated by MDM2 in cancerous cells.…”

Handling complexity in biological interactions

“…Allosteric drugs may exhibit strategic advantages; in particular, allosteric ligands do not have to compete with natural ligands for binding to the orthosteric site in the protein target, and they may show better target specificity and selectivity profile provided that allosteric sites seem to be less conserved than orthosteric sites [50]. Allosteric drugs may be even more important in the case of targeting protein-protein interactions, fundamental elements in a wide range of biological processes, which, due to their large, shallow, and featureless binding interfaces, are quite challenging for small molecule drug design [53].…”