Antibody-Constrained Protein Screening for Drug Discovery
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Solution Overview
Problem
Traditional methods for identifying compounds that modify protein function are limited by the need to screen with recombinant 'native' proteins, which restricts the discovery of compounds that can alter the protein's biological activity, and are hindered by the challenges of detecting small molecular weight changes in binding events due to the large molecular weight of target proteins.
Innovation Solution
Employing function-modifying antibodies with slow dissociation constants to hold proteins in specific conformations, allowing for the identification of low molecular weight compounds that bind to these conformations, thereby exposing previously occluded binding sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional screening methods using recombinant native proteins are employed, then the screening process is straightforward, but the ability to identify compounds that modify protein function is limited
Solution Approach 1:
The patent introduces an antibody as an intermediary component that binds to the target protein and induces conformational changes. This antibody mediator enables the exposure of previously occluded binding sites, allowing small molecule compounds to bind and modify protein function that would otherwise be inaccessible through traditional native protein screening alone
Solution Approach 2:
The patent changes the conformational state parameter of the target protein by introducing an antibody binder. This parameter change transforms the protein from its native conformation to an antibody-constrained conformation, revealing new binding sites and enabling the identification of function-modifying compounds that target these exposed sites
2Measurement precision
If small molecular weight compounds are screened against large molecular weight proteins, then the binding detection sensitivity is reduced due to negligible molecular weight change
Solution Approach 1:
The antibody serves as a mass amplifier intermediary. By binding to the small molecule compound-protein complex, the antibody adds significant molecular weight that can be detected by mass spectrometry, thereby enabling the detection of small molecule binding events that would otherwise produce negligible signal changes
Solution Approach 2:
The patent employs a nested structure where the small molecule compound binds to the target protein, and the antibody binds to the protein-compound complex. This nested arrangement allows the detection of the smallest component (compound) through the cumulative mass of the entire complex, making the binding event detectable
3Reliability
If antibodies are used as therapeutics, then high specificity and binding affinity are achieved, but oral administration is not possible and development costs are high
Solution Approach 1:
The antibody acts as a temporary intermediary tool during the drug discovery process rather than as the final therapeutic product. It enables the identification of small molecule compounds that can then serve as oral-administrable therapeutics, thus achieving the binding specificity of antibodies while avoiding their manufacturing and administration limitations
Solution Approach 2:
The patent uses the antibody-protein interaction to create a model or copy of the binding interface that exposes relevant binding sites. This allows the identification of small molecules that replicate the function-modifying effect without requiring the actual antibody structure, enabling development of more economical therapeutic alternatives
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables the identification of chemical modifiers that can bind to and alter the biological activity of proteins, overcoming the limitations of traditional screening methods by facilitating the detection of small changes in molecular weight binding events and accessing untapped areas of chemical modulators.
Implementation Method 1
antibodies can bind proteins and elicit conformational changes, for example driving the equilibrium in a given direction
Implementation Method 2
some of the function-modifying characteristics of certain antibodies are due to their ability to hold the protein in a particular conformation
Data Source
Figure 1a~1d
Figure 2a~2c
Figure 3A~3C
AI summary
The present invention relates to an improved method for drug discovery. In particular the present invention provides a method of identifying compounds capable of binding to a functional conformational state of a protein of interest or protein fragment thereof, said method comprising the steps of: (a) Binding a function-modifying antibody to the target protein of interest or a fragment thereof to provide an antibody-constrained protein or fragment, wherein the antibody has binding kinetics with the protein or fragment which are such that it has a low dissociation rate constant, (b) Providing a test compound which has a low molecular weight, (c) Evaluating whether the test compound of step b) binds the antibody constrained protein or fragment, and (d) Select a compound from step c) based on the ability to bind to the protein or fragment thereof.