Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of t...

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Autores: Cuyàs, Elisabet, Verdura, Sara, Llorach Parés, Laura, Fernández Arroyo, Salvador, Joven, Jorge, Martin Castillo, Begoña, Bosch Barrera, Joaquim, Brunet, Joan, Nonell Canals, Alfons, Sánchez Martínez, Melchor, Menendez, Javier A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172034
Acceso en línea:https://hdl.handle.net/2445/172034
Access Level:acceso abierto
Palabra clave:Diabetis
Metformina
Diabetes
Metformin
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spelling Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental ValidationCuyàs, ElisabetVerdura, SaraLlorach Parés, LauraFernández Arroyo, SalvadorJoven, JorgeMartin Castillo, BegoñaBosch Barrera, JoaquimBrunet, JoanNonell Canals, AlfonsSánchez Martínez, MelchorMenendez, Javier A.DiabetisMetforminaDiabetesMetforminMetformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD(+) binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD(+) hydrolysis product ADP-ribose, a "C-pocket"-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD(+) in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1 -activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD(+) levels decline.Frontiers Media S. A.2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfhttps://hdl.handle.net/2445/172034Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3389/fendo.2018.00657Frontiers in Endocrinology, 2018, vol. 9https://doi.org/10.3389/fendo.2018.00657cc by (c) Cuyàs et al., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1720342026-05-29T05:05:01Z
dc.title.none.fl_str_mv Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
title Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
spellingShingle Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
Cuyàs, Elisabet
Diabetis
Metformina
Diabetes
Metformin
title_short Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
title_full Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
title_fullStr Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
title_full_unstemmed Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
title_sort Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
dc.creator.none.fl_str_mv Cuyàs, Elisabet
Verdura, Sara
Llorach Parés, Laura
Fernández Arroyo, Salvador
Joven, Jorge
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Brunet, Joan
Nonell Canals, Alfons
Sánchez Martínez, Melchor
Menendez, Javier A.
author Cuyàs, Elisabet
author_facet Cuyàs, Elisabet
Verdura, Sara
Llorach Parés, Laura
Fernández Arroyo, Salvador
Joven, Jorge
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Brunet, Joan
Nonell Canals, Alfons
Sánchez Martínez, Melchor
Menendez, Javier A.
author_role author
author2 Verdura, Sara
Llorach Parés, Laura
Fernández Arroyo, Salvador
Joven, Jorge
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Brunet, Joan
Nonell Canals, Alfons
Sánchez Martínez, Melchor
Menendez, Javier A.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Diabetis
Metformina
Diabetes
Metformin
topic Diabetis
Metformina
Diabetes
Metformin
description Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD(+) binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD(+) hydrolysis product ADP-ribose, a "C-pocket"-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD(+) in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1 -activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD(+) levels decline.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/172034
url https://hdl.handle.net/2445/172034
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fendo.2018.00657
Frontiers in Endocrinology, 2018, vol. 9
https://doi.org/10.3389/fendo.2018.00657
dc.rights.none.fl_str_mv cc by (c) Cuyàs et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Cuyàs et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14 p.
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S. A.
publisher.none.fl_str_mv Frontiers Media S. A.
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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