Presenter Protein Small Molecule Complex for Undruggable Targets
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Solution Overview
Problem
Current small molecule drug discovery methods are limited in targeting proteins, as only about 10% of human proteins are considered targetable, with the remaining 90% being refractory or 'undruggable' due to their small size and inability to interact with proteins outside of hydrophobic pockets.
Innovation Solution
The method involves contacting a Test Compound with a presenter protein and a target protein, assessing the modulation of complex formation between the presenter protein and the target protein when the Test Compound is present, and identifying compounds that can form a binary complex with the presenter protein and enhance or interfere with the target protein interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If small molecules are used to target proteins, then the interaction strength is limited by adhesive forces proportional to contact surface area, but this limits the ability to target proteins outside of hydrophobic pockets
Solution Approach 1:
The patent introduces a presenting protein as an intermediary component that forms a binary complex with the small molecule. This complex then binds to target proteins that would otherwise be inaccessible to small molecules alone. The presenting protein acts as a mediator that enables high-affinity binding to previously 'undruggable' targets by providing additional interaction surfaces and enabling binding at polar/charged interfaces rather than requiring hydrophobic pockets.
2Reliability
If only 10% of human proteins are targetable by small molecules, then current drug discovery methods are effective for a limited subset of proteins, but the remaining 90% are considered refractory or intractable
Solution Approach 1:
The patent creates a universal platform (presenting protein-small molecule complex) that can be applied to a broad range of previously intractable protein targets. The presenting protein serves multiple functions: it binds the small molecule with high affinity, presents it to diverse target proteins, and enables modulation of various protein functions. This multi-functional system expands drug targetability from the limited 10% of proteins with hydrophobic pockets to potentially the remaining 90% of human proteins.
3Strength
If small molecules bind to target proteins through hydrophobic pockets via adhesive forces, then binding affinity is achieved through engulfment, but this strategy cannot bind to proteins outside of hydrophobic pockets
Solution Approach 1:
The patent creates a composite binding system consisting of a small molecule bound to a presenting protein. This composite structure combines the high-affinity binding capabilities of the small molecule with the surface area and chemical diversity of the presenting protein. The resulting binary complex can engage target proteins through multiple interaction modes including polar and charged interfaces, not limited to hydrophobic pockets. This composite approach enables binding to a broader range of protein surfaces with flexible binding mechanisms.
Data Source
AI summary
Disclosed herein are methods for identifying novel drug candidates.