The Challenge:
Molecular glue (MG), as an innovative modality, holds significant potential in drug discovery. MGs can be characterized by distinct binding and kinetic pathways that result in ternary complex formation. Currently, the prospective and rationale discovery of MG is still in its infancy, and there is a lack of comprehensive theoretical models to answer the key questions: What do the best MG opportunities look like? When is the risk too high to initiate a MG project?
The Goal:
To develop a computational model based on MG ternary binding and kinetics, to guide decision making on project initiation, and key optimization strategies
The Solution:
We are seeking proposals to achieve the goal above, by considering following points:
- Two major kinetic paths for ternary complex formation
- For each path consider following factors to predict key outcomes including 1) level of POI (protein of interest) degradation achievable, to guide MG project go/no-go; and 2) understanding dominant factor(s) driving the level of POI degradation, to guide optimization strategy
- Effector protein (EP), POI expression ratio
- EP-POI binding kinetics and affinity
- EP, POI turnover rate
- MG binary binding kinetics, affinity, and ternary binding kinetics, affinity
- Apply literature examples to validate the model (e.g. GluN2B-ifenprodil-GluN1, FKBP12-rapamycin-FRAP, CRBN-IMID-IKZF systems)
