The oxidative stress response pathway is one of the hotspots of current pharmaceutical research. Many proteins involved in these pathways work through protein-protein interactions (PPIs). Hence, targeting PPI to develop drugs for an oxidative stress response is a promising strategy. In recent years, small molecules targeting protein-protein interactions (PPIs), which provide efficient methods for drug discovery, are being investigated by an increasing number of studies. However, unlike the enzyme-ligand binding mode, PPIs usually exhibit large and dynamic binding interfaces, which raise additional challenges for the discovery and optimization of small molecules and for the biochemical techniques used to screen compounds and study structure-activity relationships (SARs). Currently, multiple types of PPIs have been clustered into different classes, which make it difficult to design stationary methods for small molecules. Deficient experimental methods are plaguing medicinal chemists and are becoming a major challenge in the discovery of PPI inhibitors. In this review, we present current methods that are specifically used in the discovery and identification of small molecules that target oxidative stress-related PPIs, including proximity-based, affinity-based, competition-based, structure-guided, and function-based methods. Our aim is to introduce feasible methods and their characteristics that are implemented in the discovery of small molecules for different types of PPIs. For each of these methods, we highlight successful examples of PPI inhibitors associated with oxidative stress to illustrate the strategies and provide insights for further design.
Keywords: Nrf2; oxidative stress response; protein-protein interaction.