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<p>Renieramycins are tetrahydroisoquinoline alkaloids derived from marine blue sponge Xestospongia. They have biological activities like herbal isoquinolones including anticancer potency along with having a characteristic nitrile group in their chemical structure that makes them good candidates for making covalent bonding with target proteins. Cancer as a multi-component disease still requires further research to find natural products interacting with several targets to suppress its’ proliferation. In this study, Network pharmacology has been employed as an efficient tool to explore the potential covalent inhibition propensity and multi-target engagement of Renieramycins within cancer-associated pathways. The plotted Protein-Protein interaction network revealed 29 possibly common targets. The KEGG analysis of Top-five ranked proteins showed that Renieramycins mainly interact with tyrosine kinase and AKT pathways that are considered essential in cancer proliferation and apoptosis. Those pathways are mainly common in lung, melanoma and prostate cancers suggesting the potential efficiency of Renieramycins against those cancers. Molecular docking and interaction profiling of different Renieramycins against key oncogenic targets revealed strong binding affinities, particularly for Renieramycin Q and M. Electrostatic and hydrophobic surface analyses demonstrated excellent physicochemical complementarity between ligands and protein pockets. Renieramycin Q exhibited favourable interactions with PIK3CA and SRC with binding affinity − 9.0 and − 8.6&#xa0;kcal/mol. Meanwhile, Renieramycin M showed promising binding to AKT1 equivalent to -8.4&#xa0;kcal/mol. Moreover, Molecular dynamics investigations revealed that interactions were stabilized by hydrogen bonds, π–cation, and hydrophobic contacts. Regarding, conformational stability of RenQ- PIK3CA, RenQ-SRC complexes achieved fluctuation reduction by 22.6% compared to the reference compounds. Additionally, RenM-AKT1 complex showed 31% fluctuation reduction. Besides, RenQ- PIK3CA, RenQ-SRC and RenM-AKT1complexes showed reduced RMSD value by 21.6%, 13% and 12.6%. This study is the first work gathered network pharmacology, docking, and molecular dynamics (MD) simulations to study the general anticancer activity of Renieramycins. This study differs from others that have primarily focused on the therapeutic potential of Renieramycins against specific types of cancer using experimental cell lines.</p>

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Investigation of the Anticancer Potential of Thai Blue Sponge via Targeting the PI3K/AKT/SRC Signaling Pathway using Molecular Docking and Dynamic Stimulation

  • 期刊论文

  • 发表日期：

    2026年4月6日

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  • Dalia E. Ali,
  • Lamiaa R. Abdelalim,
  • Randa M. Elshazly,
  • Ibrahim Oluwatobi Kehinde,
  • Mahmoud E. S. Soliman

摘要

Renieramycins are tetrahydroisoquinoline alkaloids derived from marine blue sponge Xestospongia. They have biological activities like herbal isoquinolones including anticancer potency along with having a characteristic nitrile group in their chemical structure that makes them good candidates for making covalent bonding with target proteins. Cancer as a multi-component disease still requires further research to find natural products interacting with several targets to suppress its’ proliferation. In this study, Network pharmacology has been employed as an efficient tool to explore the potential covalent inhibition propensity and multi-target engagement of Renieramycins within cancer-associated pathways. The plotted Protein-Protein interaction network revealed 29 possibly common targets. The KEGG analysis of Top-five ranked proteins showed that Renieramycins mainly interact with tyrosine kinase and AKT pathways that are considered essential in cancer proliferation and apoptosis. Those pathways are mainly common in lung, melanoma and prostate cancers suggesting the potential efficiency of Renieramycins against those cancers. Molecular docking and interaction profiling of different Renieramycins against key oncogenic targets revealed strong binding affinities, particularly for Renieramycin Q and M. Electrostatic and hydrophobic surface analyses demonstrated excellent physicochemical complementarity between ligands and protein pockets. Renieramycin Q exhibited favourable interactions with PIK3CA and SRC with binding affinity − 9.0 and − 8.6 kcal/mol. Meanwhile, Renieramycin M showed promising binding to AKT1 equivalent to -8.4 kcal/mol. Moreover, Molecular dynamics investigations revealed that interactions were stabilized by hydrogen bonds, π–cation, and hydrophobic contacts. Regarding, conformational stability of RenQ- PIK3CA, RenQ-SRC complexes achieved fluctuation reduction by 22.6% compared to the reference compounds. Additionally, RenM-AKT1 complex showed 31% fluctuation reduction. Besides, RenQ- PIK3CA, RenQ-SRC and RenM-AKT1complexes showed reduced RMSD value by 21.6%, 13% and 12.6%. This study is the first work gathered network pharmacology, docking, and molecular dynamics (MD) simulations to study the general anticancer activity of Renieramycins. This study differs from others that have primarily focused on the therapeutic potential of Renieramycins against specific types of cancer using experimental cell lines.