Article
Version 1
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A one-dimensional semaglutide-GLP-1R-based mini static GIBAC
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Version 1
: Received: 12 June 2024 / Approved: 13 June 2024 / Online: 14 June 2024 (05:04:28 CEST)
How to cite: Li, W. A one-dimensional semaglutide-GLP-1R-based mini static GIBAC. Preprints 2024, 2024060953. https://doi.org/10.20944/preprints202406.0953.v1 Li, W. A one-dimensional semaglutide-GLP-1R-based mini static GIBAC. Preprints 2024, 2024060953. https://doi.org/10.20944/preprints202406.0953.v1
Abstract
Drug-target binding is an essential parameter in drug discovery and design to ensure drug efficacy and specificity. In 2022, the concept of a general intermolecular binding affinity calculator (GIBAC) was for the first time coined: $Kd = f(molecules, envPara)$. Technically, GIBAC represents a set of in silico approaches for structural and biophysical data generation towards a paradigm shift in precise drug discovery and design, providing a comprehensive framework for intermolecular binding affinity calculation with adequate accuracy, precision and efficiency. For the first time, this study reports a prototype of GIBAC (semaGIBAC), i.e., a one-dimensional semaglutide-GLP-1R-based mini static GIBAC, based on an experimental complex structure of semaglutide and GLP-1R. Semaglutide is a potent GLP-1 receptor agonist used to treat type 2 diabetes mellitus by regulating blood glucose levels and promoting weight loss. In 2021, a structural modification involving a Val27-Arg28 exchange was manually introduced to enhance semaglutide-GLP-1R binding affinity. This study employs a comprehensive structural and biophysical analysis aimed at thoroughly exploring the sequence space of semaglutide-GLP-1R to design analogues with improved binding affinity, leading to the identification of a promising semaglutide analogue, which binds to GLP-1R with an affinity that is more than two orders of magnitude (113.3 times) higher than native semaglutide. To sum up, this article puts forward a promising structural biophysical approach for developing GLP-1 receptor agonists with enhanced efficacy, and with a GIBAC prototype (semaGIBAC), this article argues again that the time is now ripe for the construction of a real GIBAC to be listed on the agenda of the drug discovery and design community.
Keywords
GIBAC; Intermolecular binding affinity (Kd); Structural biophysics; Synthetic data; Drug discovery \& design;
Subject
Biology and Life Sciences, Biophysics
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.
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