Recent Advances in the Design and Synthesis of Small-Molecule Inhibitors for Protein–protein Interactions

Protein–protein interactions (PPIs) govern virtually every cellular signalling cascade and represent a largely underexploited class of therapeutic targets. Historically regarded as undruggable owing to their large, flat, and dynamic binding interfaces, PPIs have yielded to innovative medicinal chemistry strategies over the past decade. This review surveys recent advances (2020–2025) in the rational design and synthesis of small molecule PPI inhibitors, with particular emphasis on hot-spot-centric fragment-based approaches, structure-based drug design exploiting cryo-electron microscopy data, macrocyclisation, stapled-peptide proteomimetics, and the integration of artificial intelligence-guided virtual screening. Key oncological targets, BCL-2 family, MDM2–p53, KRAS mutant effector complexes, and BET bromodomain interactions, are discussed alongside emerging applications in infectious disease, neurodegeneration, and inflammatory signalling. Challenges in achieving drug-like physicochemical properties, cellular permeability, and selectivity are examined in the context of beyond-Rule-of-Five chemical space. The review also highlights nanocarrier-based delivery strategies that complement inhibitor design and discusses the interplay of apoptotic and survival signalling pathways as contextual drivers of PPI target selection. Clinical progress, including FDA-approved agents and ongoing trials, is tabulated, and future directions toward degrader technologies and covalent PPI inhibitors are outlined.