INTRODUCTION:

A significant portion of the cancer burden among women worldwide is cervical cancer, which primarily affects low- and middle-income countries. Additionally, marginalised individuals in nations with abundant resources may have worse results and a higher incidence of cervical cancer¹. The cervix is a complex anatomical structure with stratified squamous epithelium in the exocervix and mucus-secreting columnar epithelium in the endocervical canal. One important region of the cervix that is especially susceptible to viral neoplastic transformation is the squamocolumnar junction of this epithelium. Cervical carcinomas include multiple histological subtypes, including adenosquamous, neuroendocrine, serous papillary, and clear cell variations ^2-4. With an estimated 530,000 new cases and 275,000 deaths annually, cervical cancer ranks as the fourth most frequent malignancy among women globally, with a general fatality proportion of 52% ⁵. The cells lining the cervix, also known as the uterine cervix, the lower portion of the uterus (womb), are where cervical cancer begins^6,7. After breast cancer, cervical cancer is the second most frequent cancer in Indonesia. About 70% of cervical cancers are discovered when they are already advanced, which results in treatment failures and has a detrimental effect on the health and quality of life of patients⁸.

A prominent fruit tree on the Arabian Peninsula, the date palm (Phoenix dactylifera L.) produces dates that have been utilised for a variety of uses throughout history⁹. The fruit clusters this plant produces are represented by the word dactylifera, which translates to "finger-bearing ¹⁰. Globally, people enjoy date fruits in numerous marketplaces. Kernels from date fruits, also known as seeds or pits, constitute 13%–15% of the total weight of the date fruit^11,12. The date palm tree (Phoenix dactylifera L.) is a cultivated monocotyledonous arboreal species. This tree yields sweet fruit, referred to as date palm fruit. Datefruit is abundant in carbohydrates, fibre, vitamins, and minerals, although fats and proteins are present in lesser quantities^13,14. The fruit comprises several phytochemicals, or secondary metabolites, including phenolic acids, flavonoids, sterols, tannins, carotenoids, and glycosides. Date fruit has been documented to demonstrate many pharmacological activities, including antioxidant, anti-inflammatory, cardioprotective, anti-apoptotic, antipyretic, anti-asthmatic, and anti-cancer effects, attributed to its metabolites^15-17. Historically, Ajwa dates were used mostly for their antioxidant, anti-inflammatory, hepatoprotective, anticancer, and cardioprotective properties¹⁸. One food that can be eaten on a daily basis is ajwa dates (Phoenix dactylifera L.), which contain bioactive components that can be used as fertilisers and as treatments for a number of illnesses¹⁹.

Quercetum, the Latin designation for the flavonoid quercetin, signifies oak forest. This is classified as a flavonol and is not produced endogenously by the human body. Quercetin is recognised for its application in the treatment of cancer, allergic responses, inflammation, arthritis, and cardiovascular diseases. The flavonoid significantly influences platelet aggregation and lipid peroxidation and promotes mitochondrial biogenesis. Quercetin is a powerful compound that can address different health-related concerns. Quercetin exhibits antioxidant effects in both in vivo and in vitro conditions. The free radical scavenging action of quercetin provides protection against several age-related diseases^20-22.

14-3-3 proteins identify protein partners that are phosphorylated at serine or threonine within certain sequence motifs across all eukaryotic organisms. The seven human 14-3-3 isoforms, designated β, γ, ε, ζ, η, σ, and τ, are distinct gene-encoded paralogs that exhibit high sequence similarity and comparable phosphopeptide-recognition mechanisms, yet they demonstrate varied expression patterns across different tissues. 14-3-3 proteins are prevalent in various human organs, with multiple isoforms consistently ranking among the top 1% of around 20,000 proteins encoded by human genes. According to the Protein Abundance Database, PAXdb3, the combined seven 14-3-3 isoforms rank among the five most prevalent protein species in platelets^23-26. The plant kingdom is an important source of herbal drugs. Even in recent years, there has been an increasing awareness about the importance of medicinal plants^27-30.

Molecular docking is a recognised, in silico, structure-based technique extensively employed in drug discovery. By anticipating ligand-target interactions at the molecular level and clarifying structure-activity correlations (SAR) without requiring prior knowledge of the chemical structures of other target modulators, docking aids in the identification of new therapeutic drugs. Docking was first developed to clarify the mechanics of molecular recognition between small and large molecules, but its uses in drug development have changed dramatically in recent years^31-37.

MATERIALS AND METHODS:

Materials:

The instruments used comprise both hardware and software components. Software the hardware comprises a collection of personal computers adept at performing molecular calculations, modelling, and pharmacokinetic profile predictions, specifically the ASUS Notebook Model X455LD, which features an Intel® Core™ i5-4210U processor with a speed range of 1.70–2.4 GHz, 4 GB of RAM, a 14-inch display, 640 GB of HDD capacity, and the Windows 10 Pro Home Basic 64-bit operating system. The molecular docking procedure employs the Notepad++ software suite, AutoDock Tools, and the Discovery Studio Visualiser tool³⁸.

Data source:

In this study, the target protein structure data was obtained from the Protein Data Bank database at https://www.rcsb.org/with PDB ID: 6ZFD. This data is the result of X-ray crystallography and crystallisation of the 14-3-3 zeta protein bound to a phosphorylated peptide from the oncoprotein E6, which plays a role in various cellular processes: signal transduction, the cell cycle, apoptosis, and protein translation. Additionally, the native ligand 2-thiohydantoin was obtained from the research conducted by Yusuf Syahril et al. (2022). Additionally, a test ligand is required whose 3D structural data is obtained from the bioactive compound of Ajwa dates (Phoenix dactylifera L) obtained from PubChem https://pubchem.ncbi.nlm.nih.gov/, namely, quercetin.


*Glycerol (GPO)*	2-Tiohidantoin

Reseptor 6ZFD	Quarcetin

Moleculer Docking:

a. Preparation of Test:

Ligan downloaded from the PubCheme website (https://pubchem.ncbi.nlm.nih.gov) in the form of a three-dimensional structure optimized using the Autodock Tools program by setting the rotable bond. The structure is then saved in *pdbqt format.

b. Protein Preparations:

The 6ZFD receptor was downloaded from the RSCB.PDB website (https://www.rcsb.org) in the *.Sdv/* 3D format. Water molecules are then removed from the structure. The protein is then charged with a Kollman charge after it is stored in the format *pdbqt.

c. Molecular docking validation

Calculate the RMSD value for each docking result for the native ligand against the receptor below:

1. Receptor 6ZFD NATIVE LIGAN GPO

X = 40 center on ligan: X = -9.543 Spacing = 0,375

Y = 40 Y = -1.78

Z = 40 Z = 20.166

2. Receptor 6ZFD NATIVE LIGAN 2-Tiohidantoin

X = 40 center on ligan : X = -0.5 Spacing = 0,375

Y = 40 Y = -2.5

Z = 40 Z = 1.0

d. Molecular Docking Process:

The molecular docking process has been performed to evaluate the binding affinity between the ligand and the 6ZFD receptor, which is the target protein in this study. Two ligands were analysed: the native ligand GPO and the flavonoid compound quercetin. The main parameters analysed are the binding energy (binding affinity/ΔG), as well as the upper bound (u.b.) and lower bound (l.b.) of the binding value, which describe the potential energy range of the docking results.

RESULTS:

The redocking results show a Root Mean Square Deviation (RMSD) value of 0.9336 Å. This value is below the common threshold of 2.0 Å used as a validity criterion in molecular docking studies. A low RMSD indicates that the ligand positions resulting from docking are very close to their original positions in the crystal structure, so this docking method can be considered valid and reliable for predicting other ligand interactions with the same receptor. Additionally, the binding energy value (ΔG) obtained from the redocking results is -2.0 kcal/mol. This value indicates that the bond between the ligand and the receptor is weak, but it is still within an acceptable range considering that the original ligand used in the crystal structure (in this case, Glycerol/GOL) is not a pharmacological ligand designed to bind strongly to the receptor, but rather an additive compound in the crystallisation process.

Figure 1: Validation of 6ZFD native ligan GPO

Figure 2. Validation of 6ZFD native ligan 2-Tiohidantoin

The validation results show that the obtained RMSD (Root Mean Square Deviation) value is 3.1293Å. RMSD is a measure of the spatial deviation between the ligand position resulting from docking and the ligand position in its original crystal structure. Generally, an RMSD ≤ 2Å is considered very satisfactory, while a value between 2 and 3Å is still acceptable. However, a value greater than 3Å, as obtained in this study, indicates that the docking method has not fully been able to represent the original ligand position. This could be caused by several factors, including improper grid box settings, high ligand flexibility, or limitations in receptor rigidity parameters. Meanwhile, the binding energy value (binding affinity/ΔG) obtained from the docking process is -2.7kcal/mol. This value indicates a relatively weak binding affinity between the ligand and the receptor. Generally, a ΔG value in the range of -7 to -10kcal/mol indicates a strong interaction, while a value above -4, as in this result, indicates that the bond formed is weak. This is understandable if the ligand used is a small molecule or does not have significant hydrophobic interactions or hydrogen bonds with the receptor's active residues.

Table 1. Binding Affinity

No	LIGAN	Reseptor 6ZFD			Rotable Bond
No	LIGAN	ΔG	u.b	l.b	Rotable Bond
1	Native Ligan GPO	-2.0	2.969	4.188	2
2	Quercetin (GB GPO)	-5.4	2.016	6.939	6

Table 2. Molecular docking simulation between candidate ligand compounds and the target receptor 6ZFD using the AutoDock Tools approach.

No	LIGAN	Reseptor 6ZFD			Rotable Bond
No	LIGAN	ΔG	u.b	l.b	Rotable Bond
1	2-Tiohidantoin	-2.7	8.567	8.887	0
2	Quercetin (2-Tiohidantoin )	-5.6	2.104	7.560	6

Table 3. Bond Interaction (Native ligan GPO and Quercetin (GB GPO))

No	LIGAN	Bond Interaction
		RECEPTOR 6ZFD
		Type of Bond	Amino Acid Bond
1	Native ligan GPO	H Bond	ASN:95
1	Native ligan GPO	Van Der Waals	LEU:129, TYR:126, LEU:98, GLU:102, SER:99
2	Quercetin (GB GPO)	H Bond	TYR:126, SER:99, ASN:95, ASP:137
		Pi-Pi T-shaped	TYR:126
		Alkyl Pi-Alkyl	ILE:141
		Van Der Waals	LEU:98, GLU:102, GLN:144, GLY:140
		Alkyl Pi-Alkyl	AG:60
		Van Der Waals	SER:64, TRP:59, GLU:131, ILE:181:GLU:180
		Van Der Waals	SER:64, TRP:59, GLU:131, ILE:181:GLU:180

Table 4. Bond Interaction (Native ligan 2- Tiohidantoin and Quercetin (2-Tiohidantoin))

NO	LIGAN	Bond Interaction
		RECEPTOR 6ZFD
		Type of Bond	Amino Acid Bond
1	Native ligan 2-Tiohidantoin	H Bond	GLN:67, ARG:60
		Van Der Waals	SER:63, TRP:59, SER:64
2	Quercetin (2-Tiohidantoin)	H Bond	GLN:67, SER:63
		Carbon H Bond	ARG:60
		Alkyl Pi-Alkyl	AG:60
		Van Der Waals	SER:64, TRP:59, GLU:131, ILE:181:GLU:180

Figure 3. Visualitation of Receptor Native Ligan GLO

Figure 4. Visualitation of Receptor Native Quercetin GLO

Figure 5. Visualitation of Receptor 2- Tiohidantoin

Figure 6. Visualitation of Receptor Quercetin (2- Tiohidantoin)

DISCUSSION:

The docking method validation was performed by redocking the original ligand found in the receptor crystal structure with PDB ID: 6ZFD. The purpose of this stage is to evaluate whether the docking method and parameters used are able to reproduce the ligand position under experimental conditions.

For the native ligand GPO, a ΔG value of –2.0 kcal/mol was obtained, with an upper bound of 2.969 and a lower bound of 4.188. This value indicates that GPO has a weak binding affinity for the 6ZFD receptor. The result is still consistent with expectations because GPO is a small molecule with only two rotatable bonds, which structurally tends to have few strong interactions, such as hydrogen or hydrophobic bonds, within the protein's active site. ßConversely, the quercetin ligand showed stronger docking results, with a ΔG value of –5.4 kcal/mol, an upper bound of 2.016, and a lower bound of 6.939. A more negative ΔG value indicates that quercetin has a higher binding affinity for the 6ZFD receptor compared to GPO. Quercetin also has 6 rotatable bonds, which allows for structural flexibility and an increased likelihood of interaction with important residues in the protein's active site, such as through hydrogen bonding or π-π stacking interactions.

This comparison shows that quercetin has better potential as an alternative ligand against the 6ZFD receptor compared to the original ligand (GPO). However, it should be noted that binding affinity values in the range of –5.0 to –7.0 kcal/mol are still categorised as having moderate affinity, so the functional validity of this compound needs to be supported by further analysis, such as molecular dynamics studies or in vitro biological tests.

In this study, molecular docking simulations were performed between candidate ligand compounds and the target receptor 6ZFD using the AutoDock Tools approach. The docking results were analysed based on the binding affinity value (ΔG), which indicates the strength of the interaction between the ligand and the receptor, as well as the number of rotatable bonds that affect the flexibility of the molecule during binding.
There are two ligands that were tested, namely 2-Thiohydantoin and Quercetin (2-Thiohydantoin complex). The binding affinity value of 2-thiohydantoin is -2.7 kcal/mol, with an upper bound energy range of 8.567 kcal/mol and a lower bound energy of 8.887 kcal/mol, and it has no rotatable bonds (0). This relatively small ΔG value indicates that the formed bonds are weak. However, the low flexibility (0 rotatable bonds) makes this compound rigid and likely to remain stable in one conformation during docking.
Meanwhile, Quercetin (2-Thiohydantoin) showed a binding affinity value of -5.6 kcal/mol, which means it has a stronger binding affinity to the receptor compared to single 2-Thiohydantoin. The energy range obtained is between 2.104 and 7.560 kcal/mol, with 6 rotatable bonds, indicating that this compound is more flexible. Higher flexibility allows for conformational adjustments of the ligand within the receptor cavity, which can enhance interaction. Compared to the single ligand 2-thiohydantoin, the quercetin-2-thiohydantoin complex shows better affinity. This indicates that the addition of the quercetin structure contributes significantly to the interaction stability of the ligand-receptor complex, even though the complex is more flexible. The ΔG value of -5.6 kcal/mol still falls within the range of moderate interaction, making this compound a potential candidate for further research as an inhibitor against the 6ZFD target. Overall, of the two ligands tested, quercetin (2-thiohydantoin) performed better in terms of interaction strength and potential affinity, making it more recommended for further research, both in advanced in silico studies such as molecular dynamics simulations and in vitro experimental tests. Bonding Interaction.

The results of the interaction analysis between the ligand and the 6ZFD receptor provide important insights into the potential affinity and stability of the complex formed. In this study, two ligands were analysed: the native GPO ligand, which naturally binds within the crystal structure, and quercetin as the test ligand. The purpose of this analysis is to determine how strong and relevant the bond interactions formed are in supporting affinity for the receptor. The native ligand GPO is known to form only one hydrogen bond with ASN:95 residue, as well as several Van der Waals interactions involving LEU:129, TYR:126, LEU:98, GLU:102, and SER:99. This result indicates that GPO has limited binding points with receptors, both in terms of quantity and the diversity of binding types. Although stable, this interaction is not complex enough and tends to be passive, which is also reflected in its relatively weak affinity value. Unlike GPO, the test ligand quercetin showed a much more complex and strong interaction profile. Quercetin forms four hydrogen bonds with the residues TYR:126, SER:99, ASN:95, and ASP:137, indicating a deeper interaction within the receptor's active site. Additionally, quercetin also forms T-shaped π-π interactions with the aromatic residue TYR:126, which is crucial for maintaining the stability of the orientation of aromatic molecules like flavonoids. Furthermore, quercetin interacts hydrophobically through alkyl and pi-alkyl bonds with the residues ILE:141 and AG:60 and forms various Van der Waals interactions with additional residues such as LEU:98, GLU:102, GLN:144, GLY:140, SER:64, TRP:59, GLU:131, ILE:181, and GLU:180. The large number of residues participating in this interaction indicates that quercetin has better penetration into the active site, as well as forming an extensive and strong interaction network. From these overall results, it can be concluded that quercetin has a significantly better binding affinity and potential compared to the native GPO ligand. The more complex interactions, the greater number of hydrogen bonds, and the presence of significant aromatic and hydrophobic interactions support quercetin's lower binding affinity value (–5.6 kcal/mol) compared to GPO (–2.7 kcal/mol). Thus, quercetin has the potential to be a promising ligand candidate for targeting the 6ZFD receptor in further studies.

The molecular docking results indicate various types of non-covalent interactions between the ligand and the 6ZFD receptor, providing insight into the stability and specificity of the ligand-receptor complex binding. The two ligands analysed in this study are 2-thiohydantoin as the native ligand and quercetin (2-thiohydantoin) as the test compound derivative.

1. Native Ligand – 2-Thiohydantoin

In the interaction results, the 2-Thiohydantoin ligand shows two dominant types of bonds:

a. Hydrogen Bond: The hydrogen bond occurs with the residues GLN:67 and ARG:60. These two residues play an important role in forming specific bonds that enhance the stability of the complex. Hydrogen bonds typically contribute significantly to the direction and strength of interactions due to their polar and selective nature.

b. Van der Waals bonds: observed with residues SER:63, TRP:59, and SER:64. This interaction is weak but significant, especially in stabilising the ligand's position within the receptor's active site through surface contact.

Overall, the bonds formed are simple and limited in number, which is consistent with the relatively low binding affinity results (ΔG = –2.7 kcal/mol). This indicates that although 2-thiohydantoin is able to interact with the receptor's active site, the strength and diversity of its binding are still limited.

2. Quercetin (2-Thiohydantoin)

Meanwhile, the quercetin (2-thiohydantoin) ligand exhibited a more complex and varied interaction pattern, including:

a. Hydrogen Bonding: Occurring with GLN:67 and SER:63, which is the same as the interactions with the native ligand, indicating that this derivative retains key interactions at the active site.

b. Carbon-Hydrogen Bond: formed with ARG:60, indicating additional weak polar interactions that help stabilise the ligand within the binding pocket.

c. Alkyl and Pi-Alkyl Bonds: occur at ARG:60, suggesting hydrophobic interactions between the aromatic ring of quercetin and the nonpolar groups of this residue's side chain.

d. Van der Waals Bonds: occur more extensively, with residues SER:64, TRP:59, GLU:131, ILE:181, and GLU:180. This indicates that the quercetin (2-thiohydantoin) ligand reaches more interaction points within the receptor's active site, which can increase the overall stability of the complex.

CONCLUSIONS:

The anti-mullerian hormone receptor has a free-binding energy value of -2.6 A, and the caffeic acid Based on these results, it can be concluded that quercetin (2-thiohydantoin) has a higher diversity and number of binding interactions compared to pure 2-thiohydantoin. This more complex binding pattern correlates positively with a better binding affinity value (ΔG = –5.6 kcal/mol), indicating a stronger and more stable interaction with the 6ZFD receptor.

CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

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Received on 30.08.2025 Revised on 22.12.2025

Accepted on 28.02.2026 Published on 01.07.2026

Available online from July 04, 2026

Research J. Pharmacy and Technology. 2026;19(7):3097-3104.

DOI: 10.52711/0974-360X.2026.00440

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