Metformin chemical structure
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Metformin Chemical Structure
Introduction to Metformin
Metformin is a widely used antidiabetic drug, primarily prescribed for the treatment of type 2 diabetes mellitus. It is a biguanide, a class of compounds derived from guanidine, and is known for its hydrophilic nature and cationic form at physiological pH 2. Beyond its antidiabetic properties, metformin has shown potential in antitumor activities and increasing survival rates in various cancers 1.
Chemical Structure and Properties
Biguanide Core
Metformin's chemical structure is characterized by a biguanide core, which consists of two guanidine groups connected by a central carbon atom. This structure is responsible for its hydrophilic nature and its existence as a cationic species at physiological pH 2. The biguanide core is crucial for its biological activity, including its interaction with various cellular targets.
Protonation States
Metformin exists in multiple protonation states, with three monoprotonated forms being particularly significant. Among these, the nonplanar tautomeric form is the most stable, as revealed by quantum chemical calculations and molecular dynamics simulations 1. The protonation state of metformin influences its interaction with biological molecules, including DNA and proteins.
Interaction with Water Molecules
Metformin forms strong hydrogen bonds with surrounding water molecules, which is a key feature of its solvation dynamics. This property contributes to its high solubility and bioavailability when administered orally 1. The extended positive charge distribution of metformin allows it to act as a permanent cationic partner, facilitating interactions with various biological targets.
Interaction with Biological Targets
DNA Binding
Metformin interacts with DNA in a nonintercalative mode, primarily binding to the minor and major grooves of DNA. This interaction is more favorable with AT-rich domains, leading to a significant decrease in the free energy of binding 1. These interactions are crucial for understanding the potential antitumor activities of metformin.
SIRT1 Activation
Recent studies have proposed that metformin acts as an agonist of SIRT1, a NAD+-dependent deacetylase. Computational modeling and dynamic simulations have shown that metformin can bind to several pockets within the SIRT1 protein, including the allosteric site and the NAD+ binding site 3. This interaction enhances the catalytic efficiency of SIRT1, which may explain some of the health benefits associated with metformin, particularly in aging and metabolic regulation.
Conclusion
Metformin's chemical structure, characterized by its biguanide core and multiple protonation states, underpins its diverse biological activities. Its ability to form strong hydrogen bonds with water molecules and interact with DNA and proteins like SIRT1 highlights its multifaceted role in both diabetes management and potential antitumor activities. Understanding these structural and interaction dynamics is crucial for optimizing its therapeutic applications.
Sources and full results
Most relevant research papers on this topic
Unique Features of Metformin: A Combined Experimental, Theoretical, and Simulation Study of Its Structure, Dynamics, and Interaction Energetics with DNA Grooves.
Metformin's unique structure and dynamics may contribute to its diverse biological activities, including its potential role in antitumor activities and cancer survival rates.
Clinical Pharmacokinetics of Metformin
Metformin's pharmacokinetics and clinical response are largely mediated by organic cation transporters, with minimal impact on lactic acidosis risk.
Rigorous Journal
Highly CitedMetformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation
Metformin acts as a direct SIRT1-activating compound, potentially providing health benefits by maintaining SIRT1 activity during aging when NAD+ levels decline.
In Vitro StudyHighly CitedMetformin in cancer.
Metformin may have potential anti-tumorgenic effects, but its effectiveness in treating cancer remains inconclusive.
Highly CitedCellular and Molecular Mechanisms of Metformin Action
Metformin's glucose-lowering effect in type 2 diabetes patients is mainly mediated through inhibition of hepatic gluconeogenesis, with a redox-dependent mechanism of action being proposed.
Literature ReviewHighly CitedMetformin: historical overview
Metformin has become the most prescribed glucose-lowering medicine worldwide for managing type 2 diabetes, with its history linked to Galega officinalis, a traditional herbal medicine in Europe.
Rigorous JournalHighly CitedMetabolic Action of Metformin
Metformin effectively suppresses hepatic glucose production, improves insulin sensitivity, and alters gut microbiota composition, maintaining intestinal barrier integrity, and reducing inflammation in type 2 diabetes patients.
The mechanisms of action of metformin
Metformin improves glucose metabolism and diabetes-related complications through multiple mechanisms, including reducing hepatic glucose production and a key role for the gut.
Rigorous JournalHighly CitedMetformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).
Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2, which may play a role in intestinal absorption and tissue distribution of metformin and other organic cations, and may be a target for drug-drug and drug-nutrient interactions.
In Vitro StudyHighly CitedCellular and molecular mechanisms of metformin: an overview.
Metformin reduces hepatic glucose production and activates AMPK, offering potential new therapeutic areas and personalized medicine in Type 2 diabetes treatment.
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