Molecular Glue Screening
Molecular glue screening is a systematic strategy for identifying or optimizing small molecules that can induce or enhance protein–protein interactions (PPIs). Unlike traditional inhibitors or agonists that typically act on a single target, molecular glues are a unique class of small molecules that function as “molecular bridges,” selectively facilitating the interaction between two proteins. This interaction can modulate cellular processes or even trigger the degradation of target proteins. By introducing a novel pharmacological modality, this approach is reshaping conventional paradigms in small-molecule drug discovery and provides new therapeutic opportunities for previously "undruggable" targets, particularly those involving protein–protein interaction interfaces. As a pivotal enabling technology, molecular glue screening is playing an increasingly prominent role in drug discovery, precision medicine, and targeted protein degradation research. Despite these advances, several challenges remain. First, the structural characteristics governing small molecule-mediated PPIs are not yet fully understood due to the inherent complexity and variability of protein–protein interfaces, making rational design and optimization of candidate compounds difficult. Second, the interactome landscape can vary significantly across different cell types or pathological conditions, thereby complicating the assessment of specificity in molecular glue screening. Moreover, the downstream functional consequences of molecular glue-induced complex formation must be rigorously validated to ensure therapeutic efficacy, safety, and stability. Consequently, advancing the standardization and systematization of molecular glue screening has become a central focus of current research in this field.
From a mechanistic perspective, molecular glues operate differently from conventional small molecules that directly inhibit or activate targets. Instead, they induce conformational changes or stabilize interaction surfaces, enabling the formation of novel complexes between proteins that otherwise do not interact or interact only weakly. These neomorphic complexes often exhibit new cellular functions, such as undergoing ubiquitination and subsequent degradation via the proteasome pathway. Based on this principle, molecular glue screening has emerged as a key technique in the selective degradation of target proteins, thereby driving rapid progress in the field of targeted protein degradation. Notably, because molecular glues do not rely on canonical binding pockets, they are particularly well-suited for modulating flat or otherwise intractable protein–protein interfaces.
Molecular glue screening typically follows two strategic approaches: rational, knowledge-based screening and high-throughput, unbiased screening. The rational approach leverages structural biology and existing pharmacological data to design and refine small molecules that may function as bridges by modeling specific protein complexes. In contrast, unbiased screening employs high-throughput platforms in cellular or in vitro systems to directly identify small molecules from large compound libraries that enhance the desired PPI. In practical applications, molecular glue screening is often integrated with degradomics, ubiquitinomics, and quantitative mass spectrometry to comprehensively characterize the affected protein complexes and associated signaling pathways, enabling the construction of a complete molecular interaction map.
In experimental design, particular attention must be given to the stability and specificity of the screening systems. Commonly used platforms include reporter gene assays, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR), and yeast two-hybrid systems, which allow monitoring of PPI changes induced by molecular glues in situ or under near-physiological conditions, thereby improving hit identification rates. To verify the biological relevance of screening hits, techniques such as site-directed mutagenesis, co-immunoprecipitation, and functional inhibition are employed to elucidate the mechanism of action and identify key residues or domains involved in glue-mediated interactions. Additionally, machine learning algorithms are increasingly utilized during data analysis to model structural features, predict binding affinities, and perform functional enrichment analysis, thereby enhancing the efficiency and precision of molecular glue screening.
Leveraging an advanced proteomics platform and extensive expertise in molecular interaction analysis, MtoZ Biolabs is dedicated to providing high-throughput and customized analytical services to support molecular glue screening and related applications.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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