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Purpose <p>Diabetes mellitus (DM) remains a major global health concern, necessitating the development of novel therapeutics that overcome the limitations of existing treatments, such as insulin resistance, weight gain, and gastrointestinal side effects. This study aimed to explore the antidiabetic potential of soy-derived isoflavones through computational approaches, focusing on their inhibitory activity against aldose reductase (AR), a key enzyme implicated in DM-associated complications.</p> Methods <p>An integrative in-silico strategy was applied, combining gene expression profiling, molecular docking, molecular dynamics (MD) simulations, and quantum chemical analyses. The GSE30529 gene expression dataset was analyzed to assess AR (<i>AKR1B1</i>) expression in diabetic renal tissues. Molecular docking, MM/PBSA, and MM/PBSA analyses were used to evaluate the binding affinity and stability of isoflavone–AR complexes. Frontier molecular orbital (FMO) analysis and Molecular Electrostatic Potential (MEP) mapping were conducted to assess electronic reactivity and interaction potential.</p> Results <p>Gene expression analysis revealed significant upregulation of the <i>AKR1B1</i> gene (LogFC = 0.85, <i>p</i> &lt; 0.05) in diabetic conditions, confirming AR as a viable target. Among the isoflavones, genistein exhibited the strongest AR binding affinity (docking score − 9.1&#xa0;kcal/mol; ΔG_binding − 20.56&#xa0;kcal/mol), with MD simulations confirming its superior structural stability compared to the apo protein and reference compound. Glycitein displayed a narrow HOMO–LUMO gap (4.42&#xa0;eV), indicating high electronic reactivity, consistent with MEP mapping results.</p> Conclusion <p>Computational findings suggest that soy isoflavones, particularly genistein and glycitein, as promising AR inhibitors. Further in-vitro, in-vivo, and clinical validation is warranted to confirm their efficacy in DM management.</p>

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Computational Insights into Aldose Reductase Inhibition by Soy Isoflavones: A Pathway To Diabetes Mitigation

  • 期刊论文

  • 发表日期：

    2025年12月13日

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  • Md. Nazim Uddin,
  • Miah Roney,
  • Jie Wang,
  • Mohd Fadhlizil Fasihi Mohd Aluwi,
  • Md. Mamunur Rashid

摘要

Purpose

Diabetes mellitus (DM) remains a major global health concern, necessitating the development of novel therapeutics that overcome the limitations of existing treatments, such as insulin resistance, weight gain, and gastrointestinal side effects. This study aimed to explore the antidiabetic potential of soy-derived isoflavones through computational approaches, focusing on their inhibitory activity against aldose reductase (AR), a key enzyme implicated in DM-associated complications.

Methods

An integrative in-silico strategy was applied, combining gene expression profiling, molecular docking, molecular dynamics (MD) simulations, and quantum chemical analyses. The GSE30529 gene expression dataset was analyzed to assess AR (AKR1B1) expression in diabetic renal tissues. Molecular docking, MM/PBSA, and MM/PBSA analyses were used to evaluate the binding affinity and stability of isoflavone–AR complexes. Frontier molecular orbital (FMO) analysis and Molecular Electrostatic Potential (MEP) mapping were conducted to assess electronic reactivity and interaction potential.

Results

Gene expression analysis revealed significant upregulation of the AKR1B1 gene (LogFC = 0.85, p < 0.05) in diabetic conditions, confirming AR as a viable target. Among the isoflavones, genistein exhibited the strongest AR binding affinity (docking score − 9.1 kcal/mol; ΔG_binding − 20.56 kcal/mol), with MD simulations confirming its superior structural stability compared to the apo protein and reference compound. Glycitein displayed a narrow HOMO–LUMO gap (4.42 eV), indicating high electronic reactivity, consistent with MEP mapping results.

Conclusion

Computational findings suggest that soy isoflavones, particularly genistein and glycitein, as promising AR inhibitors. Further in-vitro, in-vivo, and clinical validation is warranted to confirm their efficacy in DM management.