RyR1 Binding Site Identification via CryoEM and Pharmacophore Modeling
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Solution Overview
Problem
Inherited mutations and stress-induced post-translational modifications in the ryanodine receptor (RyR) lead to a Ca2+ leak, causing various diseases such as skeletal muscle myopathies, heart failure, and exercise-induced sudden death, for which existing treatments are inadequate.
Innovation Solution
Development of a composition comprising a protein complex with a synthetic compound that binds to the RyR1 protein, specifically targeting leaky RyR channels to restore normal function by predicting the docked position of target ligands using pharmacophore models and cryogenic electron microscopy analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for RyR-related diseases, then general symptom management is provided, but they fail to specifically repair leaky RyR channels
Solution Approach 1:
The patent develops compounds with specific molecular structures designed to bind preferentially to the altered conformation of leaky RyR channels. The compounds are engineered with particular pharmacophore features that match the unique binding site characteristics of mutant or post-translationally modified RyR channels, providing localized and specific therapeutic action rather than general symptom management.
Solution Approach 2:
The invention involves identifying and exploiting changes in the RyR channel's conformational parameters that occur during leakage. The compounds are designed to recognize and bind to these altered states, effectively targeting the pathological form of the channel while sparing normal channels. This parameter-based targeting enables selective repair of leaky channels.
2Reliability
If the binding site of RyR1 is targeted with synthetic compounds, then Ca2+ leak is repaired and normal channel function is restored, but the precise binding mechanism and docked position are difficult to determine
Solution Approach 1:
The patent employs computational pharmacophore modeling and molecular docking simulations before conducting experimental validation. These preliminary computational studies predict the likely binding positions and orientations of synthetic compounds within the RyR1 binding site, guiding subsequent structural biology experiments and reducing the complexity of determining precise docked positions experimentally.
Solution Approach 2:
The invention uses pharmacophore models as intermediary representations that bridge the gap between chemical structure and binding site geometry. These pharmacophore models serve as mediators that facilitate the determination of compound-docked positions by translating molecular features into spatial relationships within the binding site, making the analysis more tractable.
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
The solution effectively binds to leaky RyR channels, preferentially repairing the Ca2+ leak and restoring normal channel function, thereby preventing and treating associated disease symptoms.
Implementation Method 1
a synthetic compound, wherein the protein is a ryanodine receptor 1 protein (RyR1) or mutant thereof
Implementation Method 2
the template ligand-biomolecule structure is obtained by a process comprising subjecting a complex of the biomolecule and the template ligand to single-particle cryogenic electron microscopy analysis
Data Source
AI summary
The present disclosure relates to methods and compositions useful for the identification of a ryanodine receptor modulator binding site in ryanodine receptor type 1 (RyR1). The present disclosure also provides compositions useful for the analysis of the ryanodine receptor modulator binding site in RyR1 via cryoEM. The present disclosure further provides computational methods for identifying compounds that bind to RyR1.