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Molecular glue is a small molecule that induces or stabilizes interactions between proteins or between proteins and other biomolecules (e.g., DNA, RNA) that would not normally bind or would bind only weakly. These molecules “glue” two or more biomolecules together, often enhancing or disrupting biological functions.
Key Features of Molecular Glues:
1. Small Molecules – Typically <500 Da in size, making them drug-like.
2. Induce or Stabilize Protein-Protein Interactions (PPIs) – They can bring two proteins together or strengthen existing weak interactions.
3. Can Be Natural or Synthetic – Some are naturally occurring (e.g., cyclosporine, rapamycin), while others are designed in labs.
4. Used in Drug Development – They can modulate biological pathways by stabilizing or disrupting protein complexes.Mechanisms of Action:
– Stabilizing Weak Interactions – Some molecular glues strengthen naturally occurring but transient interactions.
– Inducing Neo-Interactions – They can force two proteins to bind that normally wouldn’t.
– Targeted Protein Degradation – Some (like thalidomide analogs) recruit E3 ubiquitin ligases to mark proteins for degradation (e.g., CRBN-based molecular glues in PROTACs).Examples of Molecular Glues:
– Immunosuppressants:
– Cyclosporine A – Glues cyclophilin to calcineurin, inhibiting T-cell activation.
– Rapamycin (Sirolimus) – Binds FKBP12 and mTOR, blocking cell growth signals.
– Cancer & Degradation Inducers:
– Lenalidomide & Pomalidomide – Recruit CRBN E3 ligase to degrade transcription factors like IKZF1/3 in multiple myeloma.
– Auxin (plant hormone) – Acts as a natural molecular glue in plants to degrade transcriptional repressors.Applications:
– Drug Discovery – Especially in targeted protein degradation (e.g., PROTACs).
– Chemical Biology – Used to study protein interactions and pathways.
– Therapeutics – Treating cancer, autoimmune diseases, and neurodegenerative disorders.Difference Between Molecular Glues & PROTACs:
– Molecular glues are usually smaller and work by directly stabilizing interactions.
– PROTACs (Proteolysis-Targeting Chimeras) are bifunctional molecules that actively recruit E3 ligases to degrade target proteins.Molecular glues represent a promising area in drug development due to their ability to modulate “undruggable” targets by manipulating protein interactions.
Answer generated by DeepSeek.
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Molecular glue refers to a small molecule that promotes or enhances the interaction between two or more proteins within a cell. Instead of directly inhibiting or activating a protein’s function like traditional drugs, molecular glues work by essentially “sticking” proteins together. This induced proximity can lead to various outcomes, most notably the targeted degradation of a disease-causing protein.
Mechanism of Action:
Induced Proximity: Molecular glues bind to the surface of one protein, inducing a conformational change or creating a new binding surface that allows it to interact with another protein that it wouldn’t normally interact with strongly, or at all.
Formation of Ternary Complexes: The molecular glue forms a bridge, creating a complex of at least three components: the glue molecule and the two interacting proteins.Diverse Outcomes: This induced protein-protein interaction can lead to different cellular effects, including:
Targeted Protein Degradation (Molecular Glue Degraders): By bringing a target protein into close proximity with an E3 ubiquitin ligase, the ligase can tag the target protein with ubiquitin. This tag signals the cell’s proteasome (the protein degradation machinery) to break down the target protein. This is a major area of interest as it allows for the degradation of previously “undruggable” proteins that lack traditional binding sites for inhibitors.
Stabilization of Protein-Protein Interactions: Some molecular glues can strengthen existing, weak interactions between proteins, potentially enhancing their normal function or leading to new functional outcomes.
Inhibition of Protein Function: By inducing an interaction, a molecular glue might sterically hinder a protein’s active site or block its interaction with its natural binding partners.Key Differences from PROTACs (Proteolysis Targeting Chimeras):
Size and Structure: Molecular glues are typically smaller, single molecules compared to PROTACs, which are larger, bifunctional molecules with two distinct binding domains connected by a linker.
Mechanism: PROTACs are designed with one end that binds to the target protein and another end that binds to an E3 ligase, physically linking them together. Molecular glues, on the other hand, work by modifying the surface of one protein to promote interaction with another.Advantages of Molecular Glues:
Targeting “Undruggable” Proteins: They can induce the degradation of proteins that lack well-defined binding pockets required for traditional small molecule inhibitors.
Potent Activity: By triggering catalytic protein degradation, a single molecular glue molecule can lead to the destruction of many target protein molecules.
Potentially Better Drug Properties: Their smaller size often leads to better cell permeability, oral absorption, and blood-brain barrier penetration compared to larger molecules like PROTACs.Examples of Molecular Glues:
Thalidomide, Lenalidomide, and Pomalidomide (IMiDs): These drugs are well-known examples that work by binding to the E3 ligase cereblon and promoting the degradation of specific transcription factors like IKZF1 and IKZF3, which are important in multiple myeloma.
Cyclosporin A and FK506: These immunosuppressants function as molecular glues by forming ternary complexes with cyclophilin/FKBP12 and calcineurin, inhibiting calcineurin activity.
Rapamycin: This immunosuppressant acts as a molecular glue by stabilizing the interaction between FKBP12 and mTOR, inhibiting mTOR signaling.
Indisulam: An anticancer aryl-sulfonamide that promotes the interaction between the RNA binding protein RBM39 and the DCAF15 E3 ligase, leading to RBM39 degradation.
(R)-CR8: A CDK inhibitor found to act as a molecular glue degrader of cyclin K.Challenges in Discovery:
– Identifying molecular glues often relies on serendipity or requires sophisticated screening methods to detect the formation of ternary complexes and the resulting biological effects.
– Predicting how a small molecule will alter protein surfaces to induce new interactions is complex.Despite the challenges, molecular glues represent a promising frontier in drug discovery, offering new avenues to target disease-causing proteins and develop novel therapeutics for various conditions, including cancer, inflammatory diseases, and neurodegenerative disorders.
This answer was prepared using Gemini AI.
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Molecular glue refers to small molecules that enhance or stabilize protein-protein interactions within cells. These compounds can either induce new interactions or strengthen existing ones, offering a unique approach to drug discovery. They are particularly useful for targeting proteins that were previously considered “undruggable,” and have potential applications in treating diseases like cancer and neurodegenerative disorders.
Mechanism of Action:
– Induced Proximity: Molecular glues bind to one protein, altering its surface to create a new binding site or enhance an existing one. This allows it to interact with another protein that it wouldn’t normally bind to strongly—or at all.
– Formation of Ternary Complexes: These molecules act as a bridge, forming a complex that includes the glue molecule and the two interacting proteins.
– Targeted Protein Degradation: Some molecular glues recruit E3 ubiquitin ligases to tag a target protein with ubiquitin. This tag signals the proteasome (the cell’s protein degradation machinery) to break down the target protein. This is particularly useful for degrading “undruggable” proteins.Outcomes:
– Stabilization of Protein-Protein Interactions: They can strengthen weak interactions, enhancing normal protein functions or creating new ones.
– Inhibition of Protein Function: By inducing interactions, molecular glues might block a protein’s active site or prevent it from binding to its natural partners.Applications:
– Drug Discovery: They are pivotal in developing therapies for diseases like cancer, autoimmune disorders, and neurodegenerative conditions.
– Chemical Biology: Used to study protein interactions and pathways.Examples:
– Thalidomide and its analogs (Lenalidomide, Pomalidomide): These drugs recruit E3 ligases to degrade specific transcription factors, aiding in cancer treatment.
– Cyclosporin A and FK506: Immunosuppressants that form complexes with proteins to inhibit immune responses.
– Rapamycin: Stabilizes interactions between proteins to block cell growth signals.Advantages:
1. Targeting “Undruggable” Proteins: Molecular glues can modulate proteins that lack traditional binding sites, making them valuable for addressing previously “undruggable” targets.2. Catalytic Efficiency: A single molecule of molecular glue can induce the degradation of multiple target protein molecules, amplifying its therapeutic effect.
3. Small Size: Their compact structure often leads to better cell permeability, oral bioavailability, and the ability to cross the blood-brain barrier.
4. Versatility: They can stabilize or induce protein-protein interactions, leading to diverse therapeutic outcomes, such as targeted protein degradation or functional enhancement.
5. Broad Applications: Useful in treating cancer, autoimmune diseases, and neurodegenerative disorders, as well as in chemical biology for studying protein interactions.
Limitations:
1. Discovery Challenges: Identifying effective molecular glues often relies on serendipity or sophisticated screening methods, making the discovery process complex and resource-intensive.2. Predictability Issues: It is difficult to predict how a small molecule will alter protein surfaces to induce new interactions, complicating the design process.
3. Limited Targets: While they expand the range of druggable proteins, not all proteins can be targeted by molecular glues, and their applicability is still being explored.
4. Potential Off-Target Effects: Inducing unintended protein-protein interactions could lead to undesirable side effects or toxicity.
5. Chemical Sensitivity: Molecular glues are highly sensitive to chemical modifications, which can affect their activity and stability.
Despite these challenges, molecular glues represent a groundbreaking approach in modern drug development.
Answered using Microsoft Copilot.
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