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<p>Understanding the mechanism of action of anticancer agent plays a key role in effective clinical application of natural products. This study aims to identify an anti-cancer phytochemical with multi-target inhibition potential against non-small cell lung cancer. This study employs virtual screening of 8352 phytochemicals by molecular docking (AutoDock Vina &amp; SeeSAR) to identify potential inhibitor of KRas, SMYD3, ALDH1 and GFPT2 proteins. Molecular Dynamics Simulation (Desmond) simulation for extensive 500&#xa0;ns duration was performed to validate the inhibition potential. Followed by cell biology studies i.e., MTT assay, Flowcytometry and qRT-PCR analysis to confirm the mechanism of action. Molecular Docking and Molecular Dynamics Simulation studies predicted Heptadecanol as potential inhibitor of three drug targets, i.e., KRas, SMYD3 and GFPT2. In-vitro cytotoxicity assay confirmed the anti-cancer cytotoxicity of Heptadecanol with a significant IC<sub>50</sub> value of 3.12&#xa0;µg/ml selectively target cancer cells (A549), without substantial toxicity to non-cancerous cells (L929) with IC<sub>50</sub> of &gt; 100&#xa0;µg/ml. Flowcytometry analysis with Annexin-V and Propedium Iodide staining further confirmed the apoptotic potential of Heptadecanol against A549 cells. qRT-PCR analysis demonstrated a robust increase in GFPT2 (25.6 × fold) and SMYD3 (16.98 × fold) gene expression, that conclusively confirmed the multi-target inhibition potential of Heptadecanol. Results of the study concludes that Heptadecanol is a significant inhibitor of GFPT2 and SMYD3 protein, there by exhibiting selective anti-cancer activity against the investigated non-small cell lung cancer cells. Further in-vivo studies are in demand to quantify the anti-cancer efficacy in a living system.</p>

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“Heptadecanol” a phytochemical multi-target inhibitor of SMYD3 & GFPT2 proteins in non-small cell lung cancer: an in-silico & in-vitro investigation

  • 期刊论文

  • 发表日期：

    2025年7月14日

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  • Lokesh Ravi,
  • Pratishtha Jain,
  • Ajith Kumar K,
  • Jeevan Kumar M,
  • Mukti Panda,
  • Harshitha S,
  • Mohammed Abdul Kareem,
  • K. Sivani Yelchuri Sai,
  • Ayman Fathima,
  • V. Jensha,
  • Adarsh Anurag Rai,
  • Hida Amal Faizal,
  • Shrivats S R,
  • Ankitha Ajith,
  • Derick Yesudas,
  • Vaarruni S,
  • Varshini S,
  • Raksha Shetty,
  • Aditi Jha,
  • Gundlapalli Saradha Janaki,
  • Varsha Hannah George,
  • Stalin Nithaniyal,
  • Mookkandi Palsamy Kesavan,
  • Sajith Ahamed A,
  • Sankara Narayanan A

摘要

Understanding the mechanism of action of anticancer agent plays a key role in effective clinical application of natural products. This study aims to identify an anti-cancer phytochemical with multi-target inhibition potential against non-small cell lung cancer. This study employs virtual screening of 8352 phytochemicals by molecular docking (AutoDock Vina & SeeSAR) to identify potential inhibitor of KRas, SMYD3, ALDH1 and GFPT2 proteins. Molecular Dynamics Simulation (Desmond) simulation for extensive 500 ns duration was performed to validate the inhibition potential. Followed by cell biology studies i.e., MTT assay, Flowcytometry and qRT-PCR analysis to confirm the mechanism of action. Molecular Docking and Molecular Dynamics Simulation studies predicted Heptadecanol as potential inhibitor of three drug targets, i.e., KRas, SMYD3 and GFPT2. In-vitro cytotoxicity assay confirmed the anti-cancer cytotoxicity of Heptadecanol with a significant IC50 value of 3.12 µg/ml selectively target cancer cells (A549), without substantial toxicity to non-cancerous cells (L929) with IC50 of > 100 µg/ml. Flowcytometry analysis with Annexin-V and Propedium Iodide staining further confirmed the apoptotic potential of Heptadecanol against A549 cells. qRT-PCR analysis demonstrated a robust increase in GFPT2 (25.6 × fold) and SMYD3 (16.98 × fold) gene expression, that conclusively confirmed the multi-target inhibition potential of Heptadecanol. Results of the study concludes that Heptadecanol is a significant inhibitor of GFPT2 and SMYD3 protein, there by exhibiting selective anti-cancer activity against the investigated non-small cell lung cancer cells. Further in-vivo studies are in demand to quantify the anti-cancer efficacy in a living system.