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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design
Alistair O'Brien1, Stephen P Andrews2, Asma H Baig1
1Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6DG, United Kingdom.
Bioorganic & Medicinal Chemistry Letters
|August 27, 2019
Summary
Researchers developed novel allosteric antagonists for the glucagon-like peptide-1 receptor (GLP-1R), like HTL26119. These compounds were identified using structure-based drug design targeting unique receptor differences for selectivity.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Structural Biology
Background:
- The glucagon-like peptide-1 receptor (GLP-1R) is a key target for metabolic disease therapies.
- Allosteric modulators offer potential for improved therapeutic selectivity and reduced side effects.
- Understanding receptor structure is crucial for designing targeted therapeutics.
Purpose of the Study:
- To describe novel allosteric antagonists of the GLP-1 receptor.
- To detail the structure-based drug design (SBDD) approach for identifying these antagonists.
- To highlight the strategy for achieving GLP-1R selectivity over related receptors.
Main Methods:
- Structure-based drug design (SBDD) was employed.
- Leveraged structural insights from the related Glucagon receptor (GCGR).
- Exploited homology between GCGR and GLP-1R, focusing on key differentiating residues like C3476.36b.
Main Results:
- A series of novel allosteric GLP-1R antagonists were identified.
- HTL26119 is presented as an exemplified compound from this series.
- The design strategy successfully targeted a region critical for GLP-1R selectivity.
Conclusions:
- Novel allosteric antagonists of the GLP-1 receptor have been successfully developed.
- SBDD, informed by GCGR structure and homology, is an effective strategy for GLP-1R antagonist discovery.
- Targeting specific receptor differences enables the development of selective GLP-1R modulators.
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