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Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions

Giuseppe Floresta Orcid Logo, Davide Arillotta Orcid Logo, Valeria Catalani Orcid Logo, Gabriele Duccio Papanti Pelletier, John Martin Corkery Orcid Logo, Amira Guirguis Orcid Logo, Fabrizio Schifano Orcid Logo

Scientia Pharmaceutica, Volume: 92, Issue: 2, Start page: 17

Swansea University Author: Amira Guirguis Orcid Logo

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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...

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Published in: Scientia Pharmaceutica
ISSN: 2218-0532
Published: MDPI AG 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa65869
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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. 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spelling v2 65869 2024-03-20 Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions b49270b9a0d580cf4f31f9a1b6c93f87 0000-0001-8255-0660 Amira Guirguis Amira Guirguis true false 2024-03-20 PHAR 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. Journal Article Scientia Pharmaceutica 92 2 17 MDPI AG 2218-0532 calmoduline; semaglutide; GLP1; addiction; appetite behaviour; ligand-based computational drug design 22 3 2024 2024-03-22 10.3390/scipharm92020017 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University Another institution paid the OA fee The study was carried out with internal support from the University of Hertfordshire (GL11101336—Centre Clinical and Health Services QR). 2024-04-17T15:54:30.5417257 2024-03-20T07:53:02.5331749 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Giuseppe Floresta 0000-0002-0668-1260 1 Davide Arillotta 0000-0002-8843-0595 2 Valeria Catalani 0000-0001-6338-8653 3 Gabriele Duccio Papanti Pelletier 4 John Martin Corkery 0000-0002-3849-817x 5 Amira Guirguis 0000-0001-8255-0660 6 Fabrizio Schifano 0000-0002-4178-5401 7 65869__29888__a12011839707406a9cbee8b0cfd675b0.pdf 65869.pdf 2024-04-03T13:56:18.1999543 Output 2515240 application/pdf Version of Record true This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. true eng https://creativecommons.org/licenses/by/4.0/
title Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
spellingShingle Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
Amira Guirguis
title_short Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
title_full Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
title_fullStr Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
title_full_unstemmed Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
title_sort Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions
author_id_str_mv b49270b9a0d580cf4f31f9a1b6c93f87
author_id_fullname_str_mv b49270b9a0d580cf4f31f9a1b6c93f87_***_Amira Guirguis
author Amira Guirguis
author2 Giuseppe Floresta
Davide Arillotta
Valeria Catalani
Gabriele Duccio Papanti Pelletier
John Martin Corkery
Amira Guirguis
Fabrizio Schifano
format Journal article
container_title Scientia Pharmaceutica
container_volume 92
container_issue 2
container_start_page 17
publishDate 2024
institution Swansea University
issn 2218-0532
doi_str_mv 10.3390/scipharm92020017
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
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description 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.
published_date 2024-03-22T15:54:27Z
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