Natural products as hidden molecular glues: a new framework for multi-target traditional medicines

Abstract

Molecular glues (MGs) are small molecules that modulate protein – protein interactions by inducing or stabilizing ternary complexes, thereby reprogramming cellular networks rather than inhibiting single targets. Natural products, shaped by evolutionary selection and characterized by exceptional structural diversity, constitute a rich and underexplored source of glue-like compounds. Here, we propose a conceptual framework for rationalizing the multi-target efficacy of traditional medicines through molecular glue mechanisms. Diverse classes of natural products, including polyketides, terpenoids, steroids, lignans, organic acids, and alkaloids, have been shown to promote proximity-driven regulation of signaling pathways and targeted protein degradation. This interaction-based mode of action provides a molecular explanation for the systems-level therapeutic effects of traditional formulations that act through multiple pathways simultaneously. Integration of molecular glue theory with network pharmacology and modern chemical biology approaches offers a strategy to decode the complex pharmacology of herbal medicines and to expand the druggable proteome. Advances in proximity-based screening technologies and machine learning are expected to further accelerate the discovery of natural product-derived molecular glues for next-generation therapeutics.