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<p>Herein, nine coumarins were isolated and characterized from <i>Ammi visnaga</i>, prompting a comprehensive evaluation of their pharmacological potential. An in silico target selection approach was initially employed to identify plausible protein targets, which, combined with a repurposing rationale, prioritized squalene epoxidase (SQLE) for detailed investigation. <i>The </i>in vitro SQLE inhibition assay demonstrated that khellin, khellol, and visnagin exhibited low‐micromolar IC<sub>50</sub> values (3.48 ± 0.23, 2.83 ± 0.18, and 2.74 ± 0.15µM, respectively), rivaling the reference inhibitor (2.75 ± 0.20µM). Enzyme‐ kinetic studies confirmed a competitive inhibition mechanism, with <i>K</i><sub>i</sub> values in the low micromolar range. Subsequent docking and molecular dynamics simulations corroborated these findings, revealing that each active coumarin remains stably engaged within the SQLE active site. Free‐energy analyses (MM/PBSA) further underscored their favorable binding energetics, while free‐energy landscape (FEL) calculations indicated well‐defined and energetically accessible conformations for the inhibitor–enzyme complexes. Moreover, key structural and energetic MD parameters collectively demonstrated stable interactions and minimal perturbations to the enzyme’s global fold. An ADMET assessment revealed high oral absorption potential, no immediate concerns regarding P‐glycoprotein efflux, and generally favorable physicochemical characteristics, despite some predicted inhibitory activity against specific cytochromeP450 isoforms. Overall, these data suggest that naturally derived coumarins from <i>Ammi visnaga</i>—especially khellol, khellin, and visnagin—can effectively target SQLE, highlighting their potential for antifungal and possibly anticancer applications. This study illustrates the value of integrating phytochemical isolation, in silico repurposing, enzyme‐based screening, and advanced MD simulation workflows to accelerate the discovery of promising new inhibitors from medicinal plants.</p>

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Repurposing Ammi visnaga Furanocoumarins as Potent Squalene Epoxidase Inhibitors to Disrupt Lipid Metabolism: An Integrated Phytochemical, In Vitro, and In Silico Study

  • 期刊论文

  • 发表日期：

    2025年12月10日

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  • Emadeldin M. Kamel,
  • Doaa A. Abdelrheem,
  • Fahad M. Alshabrmi,
  • Maha A. Alwaili,
  • Faris F. Aba Alkhayl,
  • Al Mokhtar Lamsabhi

摘要

Herein, nine coumarins were isolated and characterized from Ammi visnaga, prompting a comprehensive evaluation of their pharmacological potential. An in silico target selection approach was initially employed to identify plausible protein targets, which, combined with a repurposing rationale, prioritized squalene epoxidase (SQLE) for detailed investigation. The in vitro SQLE inhibition assay demonstrated that khellin, khellol, and visnagin exhibited low‐micromolar IC50 values (3.48 ± 0.23, 2.83 ± 0.18, and 2.74 ± 0.15µM, respectively), rivaling the reference inhibitor (2.75 ± 0.20µM). Enzyme‐ kinetic studies confirmed a competitive inhibition mechanism, with Ki values in the low micromolar range. Subsequent docking and molecular dynamics simulations corroborated these findings, revealing that each active coumarin remains stably engaged within the SQLE active site. Free‐energy analyses (MM/PBSA) further underscored their favorable binding energetics, while free‐energy landscape (FEL) calculations indicated well‐defined and energetically accessible conformations for the inhibitor–enzyme complexes. Moreover, key structural and energetic MD parameters collectively demonstrated stable interactions and minimal perturbations to the enzyme’s global fold. An ADMET assessment revealed high oral absorption potential, no immediate concerns regarding P‐glycoprotein efflux, and generally favorable physicochemical characteristics, despite some predicted inhibitory activity against specific cytochromeP450 isoforms. Overall, these data suggest that naturally derived coumarins from Ammi visnaga—especially khellol, khellin, and visnagin—can effectively target SQLE, highlighting their potential for antifungal and possibly anticancer applications. This study illustrates the value of integrating phytochemical isolation, in silico repurposing, enzyme‐based screening, and advanced MD simulation workflows to accelerate the discovery of promising new inhibitors from medicinal plants.