Molecular Glue Drug Discovery Services

Molecular glues are small molecules that either stabilise an existing protein-protein interaction or induce a new interaction between two proteins. By promoting the formation of a protein complex, they can modulate biological pathways that may be difficult to address using conventional small-molecule approaches.

Although both approaches can be used for targeted protein degradation, molecular glues are typically single, low-molecular-weight compounds that induce highly cooperative interactions between proteins. In contrast, PROTACs^® are larger bifunctional molecules containing two ligands connected by a linker. The smaller size of molecular glues can offer advantages in terms of physicochemical properties, synthesis, and potential oral or CNS exposure.

Yes. Molecular glues can enable the modulation of proteins that lack conventional small-molecule binding pockets by inducing or stabilising protein-protein interactions. This creates opportunities to address challenging targets that may not be accessible through traditional drug discovery approaches. 

Not necessarily. Molecular glues can either stabilise an existing protein–protein interaction, including very weak or transient interactions, or induce a new interaction between proteins that would not normally associate strongly under physiological conditions. In many discovery programmes, the objective is to identify compounds that enhance the cooperativity of a weak interaction, effectively increasing ternary complex formation and driving the desired biological outcome.

Many molecular glue discovery programmes focus on identifying compounds that increase the cooperativity of weak or transient protein-protein interactions. Domainex uses screening platforms such as Spectral Shift (MST), HTRF, AlphaScreen, SPR, GCI and Mass Photometry to detect and characterise these compound-induced ternary complexes.

Domainex supports the full discovery cycle, including hit identification, hit validation, mechanism-of-action studies, medicinal chemistry optimisation, structural biology, biophysical characterisation, and cellular assay development. Project strategies are tailored to the scientific objectives of each client programme. 

We use a range of hit finding approaches, including fragment-based, virtual, and high throughput screening. Spectral Shift (MST), AlphaScreen, and other biochemical or biophysical assays are developed to detect cooperative ternary complex formation. These platforms can be adapted to the specific biology and target pair involved in the project. 

Domainex routinely employs orthogonal biophysical methods including Grating-Coupled Interferometry (GCI), Surface Plasmon Resonance (SPR), Mass Photometry, and other complementary technologies to characterise binding affinity, kinetics, cooperativity, and ternary complex formation. 

Yes. Structural insights are often critical for understanding molecular glue mechanisms and guiding optimisation. Domainex offers X-ray crystallography and cryo-EM capabilities to determine ternary complex structures and support structure-based drug design. Domainex also can access HDX-MS which can be employed if the other structural methods are not suitable. 

Yes. Domainex's protein science team has extensive experience producing and characterising E3 ligases, and we maintain in-house capability with commonly used ligases such as VHL and Cereblon to accelerate project initiation. 

Absolutely. We routinely conduct cell-based studies, including HiBiT degradation assays, automated Western blotting, and other cellular approaches to confirm target engagement, degradation, and biological activity in relevant cellular models. 

The optimal starting point varies by project. We can work with a validated target, an existing biological hypothesis, a known protein-protein interaction, or a targeted protein degradation concept. Our scientists will work with you to define the most appropriate discovery strategy based on your objectives and available data. 

Domainex combines expertise in molecular glues, targeted protein degradation, fragment-based discovery, medicinal chemistry, protein sciences, structural biology, biophysics, and cell biology. This integrated capability enables rapid progression from hit identification through to validated lead compounds using a coordinated workflow. 

A molecular glue modifies or stabilises a protein-protein interaction. A molecular glue degrader is a specific type of molecular glue that recruits an E3 ligase to a target protein, ultimately leading to ubiquitination and degradation of the target. 

Common assays include AlphaScreen, MST/Spectral Shift, SPR, GCI, mass photometry, cellular degradation assays, and structural biology techniques such as cryo-EM and X-ray crystallography. These complementary approaches help identify, validate, and optimise molecular glue compounds.