State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

Abstract

Targeting protein-protein interactions (PPIs) has emerged as a viable approach in modern drug discovery. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. In the recent past, significant advances have been made in the development of new biological and chemical strategies to facilitate the discovery process of small-molecule PPI inhibitors. This review aims to highlight the state-of-the-art technologies and the achievements made recently in this field. The "hot spots" of PPIs have been proved to be critical for small molecules to bind. Three strategies including screening, designing, and synthetic approaches have been explored for discovering PPI inhibitors by targeting the "hot spots". Although the classic high throughput screening approach can be used, fragment screening, fragment-based drug design and newly improved virtual screening are demonstrated to be more effective in the discovery of PPI inhibitors. In addition to screening approaches, design strategies including anchor-based and small molecule mimetics of secondary structures involved in PPIs have become powerful tools as well. Finally, constructing new chemically spaced libraries with high diversity and complexity is becoming an important area of interest for PPI inhibitors. The successful cases from the recent five year studies are used to illustrate how these approaches are implemented to uncover and optimize small molecule PPI inhibitors and notably some of them have become promising therapeutics.

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

“…Recent progress in the development of inhibitors of protein-protein interactions has suggested the potential for such drugs (19–21). Our SPR data indicate that disruption of mTOR/DEPTOR binding is due to NSC 126405’s initial interactions with DEPTOR.…”

Side-Chain Conformational Preferences Govern Protein–Protein Interactions

“…1 Mimicry of protein secondary structures has led to the development of successful inhibitors of protein–protein interactions (PPIs). 2–7 To categorize complexes mediated by secondary structures and motivate subsequent design of interfacial peptidomimetics, we and others have analyzed entries in the Protein Data Bank (PDB) and cataloged high affinity secondary structure elements at interfaces. 8–11 These efforts used computational alanine scanning analysis to identify hot spot residues, residues whose mutation to alanine results in an estimated ΔΔ G of binding > 1 kcal/mol.…”

In silico identification of essential proteins in Corynebacterium pseudotuberculosis based on protein-protein interaction networks

“…Especially the non-host homologous essential proteins might serve as potential targets for inhibiting interaction class drugs [40, 86, 88]. Generally, all reported potential interactions might allow for searching small molecule inhibitors of binding interactions [45, 86, 89], making modern drug discovery research possible [90]. By knowing the interaction partners of a protein, it is hence possible to provide a systemic view of the organism [91].…”