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

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: ~ 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.