PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
An Exhaustive Exploration of the Semaglutide-GLP-1R Sequence Space towards the Design of Semaglutide Analogues with Elevated Binding Affinity to GLP-1R
Version 1
: Received: 4 May 2024 / Approved: 6 May 2024 / Online: 6 May 2024 (10:00:19 CEST)
How to cite:
Li, W. An Exhaustive Exploration of the Semaglutide-GLP-1R Sequence Space towards the Design of Semaglutide Analogues with Elevated Binding Affinity to GLP-1R. Preprints2024, 2024050258. https://doi.org/10.20944/preprints202405.0258.v1
Li, W. An Exhaustive Exploration of the Semaglutide-GLP-1R Sequence Space towards the Design of Semaglutide Analogues with Elevated Binding Affinity to GLP-1R. Preprints 2024, 2024050258. https://doi.org/10.20944/preprints202405.0258.v1
Li, W. An Exhaustive Exploration of the Semaglutide-GLP-1R Sequence Space towards the Design of Semaglutide Analogues with Elevated Binding Affinity to GLP-1R. Preprints2024, 2024050258. https://doi.org/10.20944/preprints202405.0258.v1
APA Style
Li, W. (2024). An Exhaustive Exploration of the Semaglutide-GLP-1R Sequence Space towards the Design of Semaglutide Analogues with Elevated Binding Affinity to GLP-1R. Preprints. https://doi.org/10.20944/preprints202405.0258.v1
Chicago/Turabian Style
Li, W. 2024 "An Exhaustive Exploration of the Semaglutide-GLP-1R Sequence Space towards the Design of Semaglutide Analogues with Elevated Binding Affinity to GLP-1R" Preprints. https://doi.org/10.20944/preprints202405.0258.v1
Abstract
Semaglutide is a potent GLP-1 receptor agonist used in the treatment of type 2 diabetes mellitus due to its ability to regulate blood glucose levels and promote weight loss. On July 26, 2021, with a manually defined set of computational structural and biophysical analysis, a simple Val27-Arg28 exchange was for the first time introduced in the backbone of semaglutide to strengthen the semaglutide-GLP-1R binding affinity. In this article, a comprehensive structural and biophysical analysis approach is for the first time proposed towards an exhaustive exploration of the semaglutide-GLP-1R sequence space for the design of semaglutide analogues with elevated binding affinity to GLP-1R, thereby potentially enhancing therapeutic efficacy of structurally conceivable semaglutide analogues. Through structure biophysics-based rational design and computational modeling, this article puts forward a set of semaglutide analogues and calculated their binding affinities to GLP-1R, with one particular semaglutide analogue-GLP-1R structural model reaching a Kd of 3.0 × 10-8 M, while the Kd is 3.4 × 10-6 M for the binding of native semaglutide to GLP-1. Overall, the computationally designed semaglutide analogues here constitute a hopeful approach for developing GLP-1 receptor agonists with improved efficacy for the treatment of diabetes and weight management in future.
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.
