High-Throughput Molecular Glue Discovery via Template Screening
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Solution Overview
Problem
Current methods for discovering and designing bridging molecules that induce protein-protein interactions are limited by the need for pre-selected components and lack systematic approaches, hindering the identification of new protein-protein interactions for therapeutic applications.
Innovation Solution
A high-throughput method involving the selection of a target protein, derivation of template molecules with functional groups, and screening against a library of proteins to identify bridging molecules that form recruited protein-molecule-target protein complexes, allowing for the systematic discovery of molecular glues and biological entity-protein interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current methods for discovering bridging molecules are used, then the process can be completed with pre-selected components, but the ability to identify new protein-protein interactions is limited
Solution Approach 1:
The method segments the discovery process into distinct modules: (1) selecting a target protein, (2) deriving template molecules with functional groups, (3) screening against a library of proteins, and (4) identifying bridging molecules that form ternary complexes. This segmentation allows systematic exploration of protein-protein interactions while maintaining manageability through structured workflow
Solution Approach 2:
The screening platform is designed to be universal, capable of identifying bridging molecules for any target protein without requiring pre-selection of protein partners. The method uses a common workflow that can be applied across different therapeutic areas and target classes, enabling broad discovery of new protein-protein interactions
2Productivity
If high-throughput synthesis and screening are implemented, then the optimization of linker components in PROTACs is accelerated, but the exploration of target-binding ligand and recruited-entity-binding ligand remains limited
Solution Approach 1:
Instead of starting with pre-selected ligands and optimizing linkers (the traditional approach), the invention inverts the workflow by selecting a target protein first and systematically deriving template molecules with various functional groups. This allows comprehensive exploration of different ligand components while maintaining high-throughput optimization capabilities
Solution Approach 2:
The method performs preliminary derivation of template molecules with diverse functional groups before screening. This preliminary action creates a comprehensive library of potential bridging molecules that can be systematically evaluated, enabling both rapid optimization and broad exploration of ligand components
3Loss of time
If serendipitous discovery of molecular glues is relied upon, then no systematic design approach is needed, but the time to discover therapeutic applications is significantly extended
Solution Approach 1:
The method systematically varies key parameters including target protein selection, template molecule structures, functional group types, and screening conditions. By controlling and varying these parameters in a structured manner, the method accelerates discovery while maintaining systematic rigor, reducing the time loss associated with serendipitous approaches
Data Source
AI summary
The present disclosure relates generally to biological entity-protein (e.g. protein-protein) interactions for potential therapeutic applications, and more specifically to high-throughput methods for identifying bridging molecules that induce the formation of recruited biological entity-bridging molecule-target protein complexes to effect said biological entity-protein interactions. The present disclosure also provides methods for using said bridging molecules for treatment of disorders mediated by the target protein of the recruited biological entity-molecule-target protein complex.