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Age-related diabetes, primarily type 2 diabetes mellitus (T2DM), is a global health concern characterized by chronic hyperglycemia due to insulin resistance and impaired glucose metabolism. A key mechanism involved in the regulation of glucose levels is the translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin signaling, allowing glucose uptake into cells. Dysregulation of GLUT4 is a hallmark of insulin resistance observed in T2DM. The search for effective therapeutic agents, particularly those derived from natural bioactive compounds, has gained significant attention due to their potential to modulate biological pathways with fewer side effects compared to synthetic drugs.
This study aims to explore the interaction between GLUT4 and 20 bioactive compounds that have been previously reported to have anti-diabetic and antioxidant properties. The primary objective is to identify the compound with the highest binding affinity for GLUT4, which could potentially enhance glucose uptake and regulate blood glucose levels in the context of age-related diabetes.
A molecular docking approach was employed using PyRx, a widely accepted computational tool for predicting the binding affinity between a protein and ligands. GLUT4 was selected as the target protein due to its pivotal role in glucose metabolism. The 20 bioactive compounds chosen for this study include berberine, resveratrol, curcumin, quercetin, genistein, alpha-lipoic acid, cinnamon polyphenols, ginsenosides, thymoquinone, metformin, pterostilbene, fisetin, hesperidin, mangiferin, aloe vera extract, diosgenin, sulforaphane, galegine, astragaloside IV, and gymnemic acid. These compounds were selected based on their known or hypothesized effects on glucose regulation, insulin sensitivity, and antioxidant capacity.
The molecular structures of these compounds were obtained from PubChem, and their energy-minimized conformations were docked to the GLUT4 protein, whose structure was retrieved from the Protein Data Bank (PDB). The docking was carried out in PyRx using AutoDock Vina, which calculates the binding affinity based on free energy (kcal/mol). The docking results were evaluated based on binding affinities, with more negative values indicating stronger binding.
The docking results revealed varying degrees of binding affinities between GLUT4 and the selected bioactive compounds. Metformin, a widely used anti-diabetic drug, was included as a control to compare the efficacy of natural compounds. Among the bioactive compounds, berberine, resveratrol, quercetin, and curcumin showed strong binding affinities to GLUT4, comparable to or even surpassing that of metformin. These results suggest that these natural compounds could enhance GLUT4 activity and, thus, improve glucose uptake in insulin-resistant cells.
This study highlights the potential of bioactive compounds in regulating GLUT4 function and managing age-related diabetes. Berberine, resveratrol, curcumin, and quercetin demonstrated the highest binding affinities in molecular docking, indicating their possible efficacy as therapeutic agents. Further in vitro and in vivo studies are necessary to validate these findings and to better understand the molecular mechanisms through which these compounds modulate GLUT4 activity. The identification of such compounds could provide a natural and effective means to combat age-related diabetes and its associated complications. |