Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
Open accessAbstract
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 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.
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In silico analysis suggests that metformin could directly activate SIRT1.
“in silico analysis suggests that metformin could directly activate SIRT1 (124).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [124]
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- Authors
- Cuyàs, E., Verdura, S., Llorach-Parés, L., Fernández-Arroyo, S., Joven, J., Martin-Castillo, B., Bosch-Barrera, J., Brunet, J., Nonell-Canals, A., Sanchez-Martinez, M., & Menendez, J. A.
- Affiliations
- Institut Català d'Oncologia (ES)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2018-11-06
- Volume
- 9
- Pages
- 657-657
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC6232372
- OpenAlex
- W2900318153
- Cited by
- 122
- References
- 57
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 14 · 2023: 13 · 2022: 14 · 2021: 22 · 2020: 26 · 2019: 11
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Universitat de Girona Digital Repository (Universitat de Girona) (submittedVersion, cc-by)
- Funders
- Ministerio de Ciencia e Innovación
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, SIRT1, sirtuin activation, NAD+ binding site, ADP-ribose binding, biguanides, phenformin, molecular docking, molecular dynamics simulation, NAD+ depletion, aging
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