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<p>The HPV16 E6 oncoprotein is a critical target for therapeutic intervention in cervical cancerIn this study, we investigated the interactions of linamarin and its analogues ZINC146037704, ZINC141150528 and ZINC146038957 with HPV16 E6 protein using molecular docking, dynamics, MMPBSA and ADMET predictions. Docking and MD confirmed ZINC146037704 analogue as the most favourable binding candidate with the lowest binding free energy (–74.93 ± 13.05&#xa0;kJ/mol), stable RMSD (≈0.35&#xa0;nm) and Rg (2.1988&#xa0;nm) values, and the highest number of hydrogen bonds (14), indicating strong and persistent ligand–protein interactions. Per-residue decomposition highlighted key contributions from sub-interface I, II, LxxL motif consistent with critical residues in E6-p53 interface stabilization. Ligand interactions were primarily mediated by hydrogen bonds, π-stacking, and van der Waals forces, with glycosylated moieties enhancing polar contacts and binding stability compared to the control drug, topotecan. ADMET evaluation indicated generally favourable pharmacokinetic and safety profiles, with ZINC146037704 and ZINC3984017 showing balanced properties for further development. Overall, these results identify ZINC146037704 as a promising lead molecule for targeting HPV16 E6 and provide a foundation for future experimental validation of linamarin-derived inhibitors in cervical cancer therapy.</p>

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Linamarin and its analogues as targeted therapeutic agents in cervical cancer: insights from atomistic molecular docking, dynamics and MMPBSA calculations

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Halima Kawia,
  • James Mgaya,
  • Lucas Paul

摘要

The HPV16 E6 oncoprotein is a critical target for therapeutic intervention in cervical cancerIn this study, we investigated the interactions of linamarin and its analogues ZINC146037704, ZINC141150528 and ZINC146038957 with HPV16 E6 protein using molecular docking, dynamics, MMPBSA and ADMET predictions. Docking and MD confirmed ZINC146037704 analogue as the most favourable binding candidate with the lowest binding free energy (–74.93 ± 13.05 kJ/mol), stable RMSD (≈0.35 nm) and Rg (2.1988 nm) values, and the highest number of hydrogen bonds (14), indicating strong and persistent ligand–protein interactions. Per-residue decomposition highlighted key contributions from sub-interface I, II, LxxL motif consistent with critical residues in E6-p53 interface stabilization. Ligand interactions were primarily mediated by hydrogen bonds, π-stacking, and van der Waals forces, with glycosylated moieties enhancing polar contacts and binding stability compared to the control drug, topotecan. ADMET evaluation indicated generally favourable pharmacokinetic and safety profiles, with ZINC146037704 and ZINC3984017 showing balanced properties for further development. Overall, these results identify ZINC146037704 as a promising lead molecule for targeting HPV16 E6 and provide a foundation for future experimental validation of linamarin-derived inhibitors in cervical cancer therapy.