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<p>Flavonoids are bioactive polyphenols with enzyme inhibitory properties, making them promising candidates for modulating postprandial glucose metabolism. This study evaluated twelve structurally diverse flavonoid derivatives for their inhibitory potential against pancreatic alpha-amylase and alpha-glucosidase using an integrated in silico and in vitro approach. Molecular docking revealed binding affinities ranging from − 9 to − 5&#xa0;kcal/mol, with flavan-4-ols, taxifolin, and epigallocatechin showing the strongest interactions at catalytic residues ASP197 and GLU233 (amylase) and ASP327 and ASP443 (glucosidase). Molecular dynamics simulations and free energy calculations confirmed complex stability, though correlations with in vitro data were modest. Kinetic assays demonstrated predominantly noncompetitive–uncompetitive and uncompetitive inhibition, reducing V<sub>max</sub> without altering K<sub>m</sub>. Acarbose showed a K<sub>i</sub>′ of 25 ± 0.4&#xa0;µM for amylase and a K<sub>i</sub> of 73 ± 0.5&#xa0;µM for glucosidase, while several flavonoids, including 7-hydroxyflavanone, 2′-hydroxyflavanone, 4′-hydroxyflavanone, liquiritigenin, naringenin, eriodictyol, and ampelopsin displayed lower K<sub>i</sub>′ values between 9 and 21&#xa0;µM for amylase and between 6 and 19&#xa0;µM for glucosidase, indicating stronger affinity for the enzyme–substrate complex. These results confirm that hydroxylated flavonoids preferentially target the enzyme–substrate complex through allosteric mechanisms, often surpassing acarbose in binding efficiency. The combined in silico and in vitro workflow provides a validated strategy for systematically evaluating flavonoid derivatives as potential enzyme-targeted therapeutics for diabetes management.</p>

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In silico and in vitro evaluation of flavonoid derivatives for diabetes management: molecular dynamics, and enzyme kinetics for pancreatic alpha-amylase and alpha-glucosidase

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Jamie McMillan,
  • Megan Jean Bester,
  • Zeno Apostolides

摘要

Flavonoids are bioactive polyphenols with enzyme inhibitory properties, making them promising candidates for modulating postprandial glucose metabolism. This study evaluated twelve structurally diverse flavonoid derivatives for their inhibitory potential against pancreatic alpha-amylase and alpha-glucosidase using an integrated in silico and in vitro approach. Molecular docking revealed binding affinities ranging from − 9 to − 5 kcal/mol, with flavan-4-ols, taxifolin, and epigallocatechin showing the strongest interactions at catalytic residues ASP197 and GLU233 (amylase) and ASP327 and ASP443 (glucosidase). Molecular dynamics simulations and free energy calculations confirmed complex stability, though correlations with in vitro data were modest. Kinetic assays demonstrated predominantly noncompetitive–uncompetitive and uncompetitive inhibition, reducing Vmax without altering Km. Acarbose showed a Ki′ of 25 ± 0.4 µM for amylase and a Ki of 73 ± 0.5 µM for glucosidase, while several flavonoids, including 7-hydroxyflavanone, 2′-hydroxyflavanone, 4′-hydroxyflavanone, liquiritigenin, naringenin, eriodictyol, and ampelopsin displayed lower Ki′ values between 9 and 21 µM for amylase and between 6 and 19 µM for glucosidase, indicating stronger affinity for the enzyme–substrate complex. These results confirm that hydroxylated flavonoids preferentially target the enzyme–substrate complex through allosteric mechanisms, often surpassing acarbose in binding efficiency. The combined in silico and in vitro workflow provides a validated strategy for systematically evaluating flavonoid derivatives as potential enzyme-targeted therapeutics for diabetes management.