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Eurasian Journal of
Medicine and Oncology FN3K–Nrf2 axis inhibition in breast cancer

Figure 2. Comparative structural models of human FN3K derived from
top-ranked homology templates. The figure illustrates three homology
models generated during the structure prediction of human FN3K.
Model-1 (top left): Based on a template from Arabidopsis thaliana,
showing the highest sequence identity (90.61%) and a GMQE score of
0.94, indicating high structural reliability. Model-2 (top right): Built
from a template with 38.57% sequence identity and a GMQE of 0.70.
Model-3 (bottom): Constructed using a template with 40.67% identity
and GMQE of 0.68
Abbreviations: FN3K: Fructosamine-3-kinase; GMQE: Global model
quality estimation

confirming that the model meets the validation criteria for
acceptable stereochemistry. Overall, the combination of
high sequence similarity, favorable GMQE and QMEAN
scores, and validation through PROCHECK suggests
that Model-1 is a robust and accurate representation
of the human FN3K enzyme structure. This structural Figure 3. Ramachandran plot of the modeled human FN3K structure
model (Figure 4) provides a solid foundation for further generated by PROCHECK. The plot depicts the distribution of backbone
computational and experimental studies aimed at dihedral angles (ϕ and ψ) for amino acid residues in the modeled FN3K
understanding the functional implications and potential protein. Among 309 residues, 92.8% are located within the most favored
regions, 6.8% within additionally allowed regions, and 0.4% within
applications of human FN3K. generously allowed regions. No residues were observed in disallowed
regions, indicating the stereochemical validity of the predicted protein
3.1.2. VS and docking results structure
SBVS yielded multiple candidate compounds with strong Abbreviations: FN3K: Fructosamine-3-kinase
predicted binding affinities toward FN3K, as indicated
by favorable docking scores. The selection criteria for further evaluation. Table 2 summarizes the top six docked
potential hits included both numerical docking scores and molecules, highlighting their docking scores, molecular
qualitative assessments of key ligand–protein interactions, weights, and specific amino acid interactions within the
such as hydrogen bonding, hydrophobic contacts, and π–π FN3K binding pocket. Notably, oxaliplatin, ritonavir,
stacking. Among the docked molecules, a subset exhibited lansoprazole, and capivasertib demonstrated strong
significantly higher binding affinities and more favorable interactions with key residues, such as CYS A:24, LYS A:41,
interaction profiles compared to others. To ensure the and ASP A:217 – suggesting a conserved binding motif
selection of the most potent inhibitors, a rank-based selection critical for effective FN3K inhibition.
approach was applied, wherein the top 10% of ligands or 3.1.3. ADMET analysis of hit compounds
the top 10 ranked compounds with the most negative Glide
docking scores were shortlisted. This approach ensured To further validate the potential hits, the top-ranked
that only the best-performing molecules – those predicted candidates were subjected to additional rounds of analysis.
to have the highest binding affinity – were prioritized for This included a review of their physicochemical properties

Volume 9 Issue 3 (2025) 205 doi: 10.36922/EJMO025150114