TYK2 Inhibitor Compounds for Binding-Pocket Water Displacement
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Solution Overview
Problem
There is a need for effective inhibitors of TYK2 kinase to treat various diseases and disorders associated with abnormal cellular responses triggered by kinase-mediated events, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.
Innovation Solution
Compounds are designed to displace or disrupt unstable water molecules in the TYK2 kinase binding pocket, providing tighter binding and acting as potent inhibitors of TYK2 kinase, which are administered to treat TYK2-mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds are designed to displace or disrupt unstable water molecules in the TYK2 kinase binding pocket, then binding affinity and inhibitory potency are improved, but molecular design complexity increases
Solution Approach 1:
The patent applies parameter changes by modifying molecular properties such as lipophilicity, hydrogen bonding capacity, and steric bulk to optimize displacement of unstable water molecules in the TYK2 binding pocket. Specific chemical parameters like LogP, molecular weight, and substituent patterns are tuned to achieve optimal binding affinity while maintaining drug-like properties.
Solution Approach 2:
The invention employs local quality by introducing specific functional groups and substituents at particular positions within the molecular scaffold. Different regions of the molecule are optimized for specific functions: some regions target hydrophobic pockets, others form hydrogen bonds with specific residues, and certain groups are designed to displace particular water molecules in the binding site.
2Reliability
If compounds are designed to displace or disrupt unstable water molecules in the TYK2 kinase binding pocket, then binding affinity is improved, but synthesis difficulty increases
Solution Approach 1:
The molecular structure is segmented into distinct building blocks or fragments that can be synthesized separately and then assembled through coupling reactions. This modular approach allows each fragment to be optimized for ease of synthesis while the overall molecule achieves the desired binding affinity through the specific arrangement of these segments.
Solution Approach 2:
The patent employs universal building blocks and scaffolds that can serve multiple functions both in synthesis and in binding. Certain core structures are designed to provide both synthetic accessibility and the necessary binding interactions, reducing the need for complex, specialized synthesis steps.
Data Source
AI summary
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.