Version 1
: Received: 14 June 2024 / Approved: 14 June 2024 / Online: 17 June 2024 (09:12:54 CEST)
How to cite:
Li, W. Optimizing GLP-1R Agonist: A Computational Semaglutide Analogue with 112-fold Enhanced Binding Affinity to GLP-1R. Preprints2024, 2024061032. https://doi.org/10.20944/preprints202406.1032.v1
Li, W. Optimizing GLP-1R Agonist: A Computational Semaglutide Analogue with 112-fold Enhanced Binding Affinity to GLP-1R. Preprints 2024, 2024061032. https://doi.org/10.20944/preprints202406.1032.v1
Li, W. Optimizing GLP-1R Agonist: A Computational Semaglutide Analogue with 112-fold Enhanced Binding Affinity to GLP-1R. Preprints2024, 2024061032. https://doi.org/10.20944/preprints202406.1032.v1
APA Style
Li, W. (2024). Optimizing GLP-1R Agonist: A Computational Semaglutide Analogue with 112-fold Enhanced Binding Affinity to GLP-1R. Preprints. https://doi.org/10.20944/preprints202406.1032.v1
Chicago/Turabian Style
Li, W. 2024 "Optimizing GLP-1R Agonist: A Computational Semaglutide Analogue with 112-fold Enhanced Binding Affinity to GLP-1R" Preprints. https://doi.org/10.20944/preprints202406.1032.v1
Abstract
Drug-target binding is a crucial parameter in drug discovery and design, ensuring drug efficacy and specificity. Semaglutide, a potent GLP-1 receptor agonist, is widely used to treat type 2 diabetes mellitus by regulating blood glucose levels and promoting weight loss. This study introduces a novel approach utilizing the concept of a general intermolecular binding affinity calculator (GIBAC) for designing semaglutide analogues with enhanced binding affinity to GLP-1R. For the first time, a Val27-Arg28 exchange was manually introduced to strengthen the semaglutide-GLP-1R binding affinity. A comprehensive structural and biophysical analysis was conducted to explore the semaglutide-GLP-1R sequence space, leading to the identification of promising analogues. Among these, one semaglutide analogue demonstrated a binding affinity to GLP-1R that is more than two orders of magnitude (113.3 times) higher than native semaglutide, achieving a Kd of 3.0 x 10-8 M compared to the Kd of 3.4 x 10-6 M for native semaglutide. This article proposes a promising structural biophysical approach for developing GLP-1 receptor agonists with improved efficacy. The prototype GIBAC, termed semaGIBAC, represents a paradigm shift in precise drug discovery and design, advocating for the construction of a full-scale GIBAC to be prioritized within the drug discovery and design community.
Medicine and Pharmacology, Endocrinology and Metabolism
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
