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Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
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Davide Arillotta ,
Valeria Catalani ,
Gabriele Duccio Papanti Pelletier,
John Martin Corkery ,
Amira Guirguis ,
Fabrizio Schifano
Scientia Pharmaceutica, Volume: 92, Issue: 2, Start page: 17
Swansea University Author:
Amira Guirguis
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DOI (Published version): 10.3390/scipharm92020017
Abstract
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has gained considerable at-tention as a therapeutic agent for type 2 diabetes mellitus and obesity. Despite its clinical success, the precise mechanisms underlying its pharmacological effects remain incompletely understood. In this stu...
| Published in: | Scientia Pharmaceutica |
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| ISSN: | 2218-0532 |
| Published: |
MDPI AG
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65869 |
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| Abstract: |
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has gained considerable at-tention as a therapeutic agent for type 2 diabetes mellitus and obesity. Despite its clinical success, the precise mechanisms underlying its pharmacological effects remain incompletely understood. In this study, we employed ligand-based drug design strategies to investigate potential off-target interactions of semaglutide. Through a comprehensive in silico screening of semaglutide's structural properties against a diverse panel of proteins, we have identified calmodulin (CaM) as a putative novel target of semaglutide. Molecular docking simulations revealed a strong inter-action between semaglutide and CaM, characterized by favorable binding energies and a stable binding pose. Further molecular dynamics simulations confirmed the stability of the semag-lutide-CaM complex, emphasizing the potential for a physiologically relevant interaction. In conclusion, our ligand-based drug design approach has uncovered calmodulin as a potential novel target of semaglutide. This discovery sheds light on the complex pharmacological profile of semaglutide and offers a promising direction for further research into the development of in-novative therapeutic strategies for metabolic disorders. The CaM, and especially so the CaMKII, system is central in the experience of both drug- and natural-related reward. It is here hypoth-esized that, due to semaglutide binding, the reward pathway-based calmodulin system may be activated, and/or differently regulated. This may result in the positive semaglutide action on appetitive behaviour. Further studies are are required to confirm these findings. |
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| Keywords: |
calmoduline; semaglutide; GLP1; addiction; appetite behaviour; ligand-based computational drug design |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
The study was carried out with internal support from the University of Hertfordshire (GL11101336—Centre Clinical and Health Services QR). |
| Issue: |
2 |
| Start Page: |
17 |