Allosteric Modulators for GLP-1 Receptor Small Molecule Design

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Solution Overview

Problem

Current approaches have failed to develop effective small molecule drugs that target the Glucagon-like peptide 1 receptor (GLP-1R) for the treatment of diabetes due to the large orthosteric binding site and lack of structural information on the active state of the 7TM domain of GLP-1R.

Innovation Solution

The discovery of small molecule GLP-1R agonists and positive allosteric modulators (PAMs) using structure-based molecule design, site-specific mutagenesis studies, and in vitro validation, which identify compounds like Compound Ia, Ib, and Ic that selectively enhance GLP-1R activity without affecting other G-protein-coupled receptors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If high-throughput screenings are used to identify small molecule GLP-1R agonists, then lead compounds can be discovered, but further development of the lead compounds has not been successful

Engineering Contradiction:

Improvelead compound discoveryVSAvoiddrug development success

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the binding mode parameter from orthosteric to allosteric, targeting a different site on the GLP-1R receptor. This parameter change allows small molecules to bind effectively and achieve successful drug development, resolving the failure of previous high-throughput screening approaches that targeted the orthosteric site

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses structure-based molecular design as an intermediary approach between random high-throughput screening and rational drug design. By incorporating structural information about the allosteric site, the screening process becomes more targeted and efficient, leading to successful lead compound identification and development

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If the orthosteric binding site is targeted for small molecule agonist development, then GLP-1R can be activated, but the large nature of the orthosteric binding site hinders the development of orally active small molecule agonists

Engineering Contradiction:

Improvereceptor activationVSAvoidorally active drug development

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent extracts the drug binding function from the orthosteric site and relocates it to the allosteric site. This extraction allows small molecules with favorable pharmacokinetic properties for oral administration to bind effectively, while the endogenous peptide ligand remains bound at the orthosteric site

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent transitions from targeting the conventional orthosteric binding site to targeting the allosteric site, which is located in a different spatial dimension on the receptor protein. This dimensional change enables small molecule access and binding without the steric constraints of the large orthosteric site

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

Data Source

PatentUS20220193080A1Allosteric agonists and positive allosteric modulators of glucagon-like peptide 1 receptor

Publication Date: 2022.06.23 SAINT JOSEPHS UNIV

AI summary

The present invention relates to the discovery of small molecule compounds that act as GLP-1R agonists and/or as positive allosteric modulators (PAMs) of GLP-1R. Such compounds are useful to treat, ameliorate, and/or prevent insulin resistance and/or diabetes in a mammal.