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Linamarin and its analogues as targeted therapeutic agents in cervical cancer: insights from atomistic molecular
Halima Kawia1, James Mgaya1, Lucas Paul1
1Chemistry Department, Dar es Salaam University College of Education, P.O Box 2329, Dar es Salaam, Tanzania.
Abstract:
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.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s40203-026-00619-2.
Insights
Linamarin derivatives show potential as cervical cancer therapeutics. ZINC146037704 strongly binds to the HPV16 E6 oncoprotein, a key target, with favorable drug-like properties for further development.
Area of Science:
- Biochemistry
- Computational Chemistry
- Oncology
Background:
- The human papillomavirus type 16 (HPV16) E6 oncoprotein is a crucial therapeutic target in cervical cancer.
- Linamarin and its derivatives are explored for their potential anticancer activities.
Purpose of the Study:
- To investigate the interaction of linamarin and its analogues with the HPV16 E6 oncoprotein.
- To identify promising lead compounds for cervical cancer therapy targeting HPV16 E6.
Main Methods:
- Molecular docking, molecular dynamics simulations, MM/PBSA calculations, and ADMET predictions were employed.
- Analysis focused on binding free energy, root-mean-square deviation (RMSD), radius of gyration (Rg), and hydrogen bond interactions.
Main Results:
- ZINC146037704 demonstrated the most favorable binding to HPV16 E6, exhibiting the lowest binding free energy (-74.93 ± 13.05 kJ/mol) and stable interactions.
- Key interactions involved hydrogen bonds, π-stacking, and van der Waals forces, with glycosylated moieties enhancing binding stability.
- ADMET predictions suggested favorable pharmacokinetic and safety profiles for ZINC146037704 and ZINC3984017.
Conclusions:
- ZINC146037704 is identified as a promising lead molecule for targeting HPV16 E6 in cervical cancer.
- These findings provide a basis for experimental validation of linamarin-derived inhibitors for cervical cancer treatment.
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