Hexahydropentalene LRH-1 Modulators for Consistent Receptor Binding
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Solution Overview
Problem
Current modulators for liver receptor homologue 1 (LRH-1) are limited in their ability to effectively regulate gene expression and target specific diseases such as diabetes, cancer, and cardiovascular disease, with existing agonists exhibiting variable binding modes and limited efficacy.
Innovation Solution
Development of hexahydropentalene derivatives that stabilize or destabilize the activation function surface (AFS) of LRH-1, enhancing co-activator binding and modulating LRH-1 activity through strategic interactions with specific residues, such as Thr-352, to achieve desired therapeutic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing LRH-1 agonists are used, then some therapeutic effect is achieved, but binding mode variability and limited efficacy persist
Solution Approach 1:
The patent applies local quality by designing ligands with specific functional groups positioned at precise locations to interact with particular residues (Thr-352, His-390, Arg-393) in the LRH-1 binding pocket. This localized optimization ensures consistent binding mode through specific molecular interactions while maintaining high therapeutic efficacy for metabolic diseases.
2Reliability
If LRH-1 activity is modulated to treat metabolic diseases, then therapeutic efficacy improves, but specificity and off-target effects must be controlled
Solution Approach 1:
The patent employs parameter changes by systematically varying ligand structural parameters (functional groups, stereochemistry, molecular size) to optimize binding affinity and selectivity for LRH-1. This allows tuning of therapeutic efficacy while minimizing off-target effects through precise control of molecular interaction parameters.
Data Source
AI summary
This disclosure relates to modulators of liver receptor homologue 1 (LRH-1) and methods of managing disease and conditions related thereto. In certain embodiments, modulators are derivatives of hexahydropentalene. In certain embodiments, this disclosure relates to methods of treating or preventing cancer, diabetes, or cardiovascular disease by administering an effective amount of a hexahydropentalene derivative disclosed herein.