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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

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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.

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Acknowledgements

This work was supported from the project with Ref: PID2023-150717NB-I00 (MICINN) of the Ministerio de Ciencia, Innovación y Universidades of Spain. The authors would also like to thank the Centro de Computación Científica of the UAM (CCC-UAM) for the generous allocation of computer time and for their continued technical support. The authors acknowledge Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2025R227), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Funding

This work was supported from the project with Ref: PID2023-150717NB-I00 (MICINN) of the Ministerio de Ciencia, Innovación y Universidades of Spain. The authors would also like to thank the Centro de Computación Científica of the UAM (CCC-UAM) for the generous allocation of computer time and for their continued technical support. The authors acknowledge Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2025R227), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

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  1. Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt

    Emadeldin M. Kamel & Doaa A. Abdelrheem

  2. Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, 51452, Buraydah, Saudi Arabia

    Fahad M. Alshabrmi & Faris F. Aba Alkhayl

  3. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, 11671, Riyadh, Saudi Arabia

    Maha A. Alwaili

  4. Departamento de Química and Institute for Advanced Research in Chemical Science (IAdChem), Facultad de Ciencias, Universidad Autónoma de Madrid, Módulo 13, 28049, Madrid, Spain

    Al Mokhtar Lamsabhi

Authors
  1. Emadeldin M. Kamel
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  2. Doaa A. Abdelrheem
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  3. Fahad M. Alshabrmi
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  4. Maha A. Alwaili
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  5. Faris F. Aba Alkhayl
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  6. Al Mokhtar Lamsabhi
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Contributions

Emadeldin M. Kamel: conceptualization, methodology, investigation, writing—original draft, and supervision. Doaa A. Abdelrheem: formal analysis, data curation, visualization, and investigation. Fahad M. Alshabrmi: resources, funding acquisition, project administration. Maha A. Alwaili: software, validation, methodology, and investigation. Faris F. Aba Alkhayl: investigation, in vitro experiments, data interpretation, investigation. Al Mokhtar Lamsabhi: supervision, methodology, writing—review and editing, and computational chemistry oversight.

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Correspondence to Emadeldin M. Kamel.

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Kamel, E.M., Abdelrheem, D.A., Alshabrmi, F.M. et al. Repurposing Ammi visnaga Furanocoumarins as Potent Squalene Epoxidase Inhibitors to Disrupt Lipid Metabolism: An Integrated Phytochemical, In Vitro, and In Silico Study. Mol Biotechnol (2025). https://doi.org/10.1007/s12033-025-01524-3

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