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<p>Cancer remains one of the most challenging diseases to treat, mainly due to its ability to evade apoptosis, a form of programmed cell death essential for cellular homeostasis. The Bcl-2 protein family, particularly its anti-apoptotic or pro-death members, plays a pivotal role in this evasion, with Bcl-B (BCL2L10) emerging as a significant yet unexplored druggable or therapeutic target in cancer therapy. This study utilizes comprehensive computational approaches to identify the potential mangrove-derived candidate phytochemical inhibitors of the Bcl-B protein. In the present study, we retrieved the three-dimensional structure of the anti-apoptotic Bcl-B protein from the Research Collaboratory for Structural Bioinformatics Protein Data Bank. We optimized it, resulting in enhanced structural stability and integrity following energy minimization. A customized mangrove-derived phytochemical library was created using text-mining techniques. It was sourced from two important databases: the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) and NCBI (National Center for Biotechnology Information)—PubChem. Virtual screening against the in-house mangrove library using AutoDock Vina identified promising molecules based on estimated binding affinity (<i>ΔG</i>), estimated inhibition constant (<i>Ki</i>), intermolecular interactions, and binding orientation, and they were further validated through molecular dynamics simulations using Gromacs Version 2021.3. Out of all molecules, the following two candidates (PubChem IDs: 131751260: −&#xa0;26.10 (± 3.74) and 12004512: −&#xa0;20.88 (± 2.67) kcal/mol) demonstrated strong binding to the BH3 domain of Bcl-B protein, disrupting its anti-apoptotic function by preventing the inhibition of pro-apoptotic protein partners. Triplicate MD simulations confirmed the structural stability, integrity, compactness, dynamics, and folding properties of these protein–ligand complexes, suggesting these mangrove-derived phytochemical molecules have the potential to inhibit Bcl-B activity and restore apoptotic processes in cancerous cells. Our computational findings address a significant research gap in the therapeutic targeting of the Bcl-B protein, providing a strong foundation for further experimental studies and the discovery of novel anti-cancerous molecules. By analyzing the anti-cancer properties of phytochemical molecules, this study opens new avenues for targeted cancer therapy, particularly for cancers where Bcl-B overexpression contributes to drug resistance.</p>

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Harnessing mangrove-derived phytochemicals to target Bcl-B in cancer: a computational study

  • 期刊论文

  • 发表日期：

    2026年2月14日

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  • Deepika Dhillon,
  • Sakshi Yadav,
  • Rittik Bhati,
  • Mohd Sajid Ali,
  • Hamad A. Al-Lohedan,
  • J. Senthil Kumaran,
  • Mohammad Tariq,
  • Monika Jain,
  • Amit Kumar Singh,
  • Jayaraman Muthukumaran

摘要

Cancer remains one of the most challenging diseases to treat, mainly due to its ability to evade apoptosis, a form of programmed cell death essential for cellular homeostasis. The Bcl-2 protein family, particularly its anti-apoptotic or pro-death members, plays a pivotal role in this evasion, with Bcl-B (BCL2L10) emerging as a significant yet unexplored druggable or therapeutic target in cancer therapy. This study utilizes comprehensive computational approaches to identify the potential mangrove-derived candidate phytochemical inhibitors of the Bcl-B protein. In the present study, we retrieved the three-dimensional structure of the anti-apoptotic Bcl-B protein from the Research Collaboratory for Structural Bioinformatics Protein Data Bank. We optimized it, resulting in enhanced structural stability and integrity following energy minimization. A customized mangrove-derived phytochemical library was created using text-mining techniques. It was sourced from two important databases: the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) and NCBI (National Center for Biotechnology Information)—PubChem. Virtual screening against the in-house mangrove library using AutoDock Vina identified promising molecules based on estimated binding affinity (ΔG), estimated inhibition constant (Ki), intermolecular interactions, and binding orientation, and they were further validated through molecular dynamics simulations using Gromacs Version 2021.3. Out of all molecules, the following two candidates (PubChem IDs: 131751260: − 26.10 (± 3.74) and 12004512: − 20.88 (± 2.67) kcal/mol) demonstrated strong binding to the BH3 domain of Bcl-B protein, disrupting its anti-apoptotic function by preventing the inhibition of pro-apoptotic protein partners. Triplicate MD simulations confirmed the structural stability, integrity, compactness, dynamics, and folding properties of these protein–ligand complexes, suggesting these mangrove-derived phytochemical molecules have the potential to inhibit Bcl-B activity and restore apoptotic processes in cancerous cells. Our computational findings address a significant research gap in the therapeutic targeting of the Bcl-B protein, providing a strong foundation for further experimental studies and the discovery of novel anti-cancerous molecules. By analyzing the anti-cancer properties of phytochemical molecules, this study opens new avenues for targeted cancer therapy, particularly for cancers where Bcl-B overexpression contributes to drug resistance.