Natural Product Modulators of Protein–Protein Interactions: A Comprehensive Review

ABSTRACT Introduction Natural products offer structurally diverse small molecules that modulate protein–protein interactions (PPIs) by disrupting pathogenic complexes or stabilizing beneficial ones, expanding therapeutic opportunities beyond classical enzyme inhibition. Objective This review synthesizes natural product PPI modulators, emphasizing target coverage, mechanisms of action, reported potency/affinity, structural evidence, and functional outcomes in cellular or organismal models. Methods We curated published examples of natural products acting as direct PPI inhibitors or indirect modulators and organized them by (i) functional PPI categories—oncogenic complexes (MDM2–p53, BCL‐2 family, IAP–caspase), signaling assemblies (Wnt/β‐catenin, 14‐3‐3/adaptor complexes), chaperone/co‐chaperone systems (Hsp90 and partners), and immunophilin‐mediated interactions (calcineurin–NFAT, mTOR complexes)—and (ii) mechanistic class, including competitive interface blockade, allosteric modulation, covalent modification of one partner, and stabilization via molecular glue or ternary‐complex formation. For each class, we summarize representative scaffolds and report binding affinities or IC50/Ki values and structural data when available. Results Natural products span multiple modes of PPI control and highlight tractable intervention points across diverse proteins. Representative examples include chlorofusin, a fungal metabolite that disrupts p53–MDM2 (IC 50 ~ 4.6 μM); (−)‐gossypol, a plant polyphenol acting as a BH3 mimetic that binds BCL‐xL (K i ~ 0.5 μM); celastrol, a covalent triterpenoid that impairs the Hsp90–Cdc37 complex; and cyclosporin A, FK506, and rapamycin, which form ternary complexes to reprogram immunophilin PPIs. Conclusion Collectively, these modulators demonstrate PPI druggability and provide chemical probes and lead scaffolds for therapeutic development in cancer, neurodegeneration, infectious disease, and immune disorders.