Exploring the mechanism of metformin action in Alzheimer's disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation.
Alzheimer’s disease
metformin
molecular docking
network pharmacology
type 2 diabetes
Journal
Therapeutic advances in endocrinology and metabolism
ISSN: 2042-0188
Titre abrégé: Ther Adv Endocrinol Metab
Pays: United States
ID NLM: 101532143
Informations de publication
Date de publication:
2023
2023
Historique:
received:
19
03
2022
accepted:
19
05
2023
medline:
2
10
2023
pubmed:
2
10
2023
entrez:
2
10
2023
Statut:
epublish
Résumé
Metformin, which has been shown to be highly effective in treating type 2 diabetes (T2D), is also believed to be valuable for Alzheimer's disease (AD). Computer simulation techniques have emerged as an innovative approach to explore mechanisms. To study the potential mechanism of metformin action in AD and T2D. The chemical structure of metformin was obtained from PubChem. The targets of metformin were obtained from PubChem, Pharm Mapper, Batman, SwissTargetPrediction, DrugBank, and PubMed. The pathogenic genes of AD and T2D were retrieved from the GeneCards, OMIM, TTD, Drugbank, PharmGKB, and DisGeNET. The intersection of metformin with the targets of AD and T2D is represented by a Venn diagram. The protein-protein interaction (PPI) and core targets networks of intersected targets were constructed by Cytoscape 3.7.1. The enrichment information of GO and Kyoto Encyclopedia of Gene and Genomics (KEGG) pathways obtained by the Metascape was made into a bar chart and a bubble diagram. AutoDockTools, Pymol, and Chem3D were used for the molecular docking. Gromacs software was used to perform molecular dynamics (MD) simulation of the best binding target protein. A total of 115 key targets of metformin for AD and T2D were obtained. GO analysis showed that biological process mainly involved response to hormones and the regulation of ion transport. Cellular component was enriched in the cell body and axon. Molecular function mainly involved kinase binding and signal receptor regulator activity. The KEGG pathway was mainly enriched in pathways of cancer, neurodegeneration, and endocrine resistance. Core targets mainly included TP53, TNF, VEGFA, HIF1A, IL1B, IGF1, ESR1, SIRT1, CAT, and CXCL8. The molecular docking results showed best binding of metformin to CAT. MD simulation further indicated that the CAT-metformin complex could bind well and converge relatively stable at 30 ns. Metformin exerts its effects on regulating oxidative stress, gluconeogenesis and inflammation, which may be the mechanism of action of metformin to improve the common pathological features of T2D and AD.
Sections du résumé
Background
UNASSIGNED
Metformin, which has been shown to be highly effective in treating type 2 diabetes (T2D), is also believed to be valuable for Alzheimer's disease (AD). Computer simulation techniques have emerged as an innovative approach to explore mechanisms.
Objective
UNASSIGNED
To study the potential mechanism of metformin action in AD and T2D.
Methods
UNASSIGNED
The chemical structure of metformin was obtained from PubChem. The targets of metformin were obtained from PubChem, Pharm Mapper, Batman, SwissTargetPrediction, DrugBank, and PubMed. The pathogenic genes of AD and T2D were retrieved from the GeneCards, OMIM, TTD, Drugbank, PharmGKB, and DisGeNET. The intersection of metformin with the targets of AD and T2D is represented by a Venn diagram. The protein-protein interaction (PPI) and core targets networks of intersected targets were constructed by Cytoscape 3.7.1. The enrichment information of GO and Kyoto Encyclopedia of Gene and Genomics (KEGG) pathways obtained by the Metascape was made into a bar chart and a bubble diagram. AutoDockTools, Pymol, and Chem3D were used for the molecular docking. Gromacs software was used to perform molecular dynamics (MD) simulation of the best binding target protein.
Results
UNASSIGNED
A total of 115 key targets of metformin for AD and T2D were obtained. GO analysis showed that biological process mainly involved response to hormones and the regulation of ion transport. Cellular component was enriched in the cell body and axon. Molecular function mainly involved kinase binding and signal receptor regulator activity. The KEGG pathway was mainly enriched in pathways of cancer, neurodegeneration, and endocrine resistance. Core targets mainly included TP53, TNF, VEGFA, HIF1A, IL1B, IGF1, ESR1, SIRT1, CAT, and CXCL8. The molecular docking results showed best binding of metformin to CAT. MD simulation further indicated that the CAT-metformin complex could bind well and converge relatively stable at 30 ns.
Conclusion
UNASSIGNED
Metformin exerts its effects on regulating oxidative stress, gluconeogenesis and inflammation, which may be the mechanism of action of metformin to improve the common pathological features of T2D and AD.
Identifiants
pubmed: 37780174
doi: 10.1177/20420188231187493
pii: 10.1177_20420188231187493
pmc: PMC10540612
doi:
Types de publication
Journal Article
Langues
eng
Pagination
20420188231187493Informations de copyright
© The Author(s), 2023.
Déclaration de conflit d'intérêts
The authors declare that there is no conflict of interest.
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