Indonesian Journal of Cancer Chemoprevention.
February 2025 ISSN: 2088Ae0197 e-ISSN: 2355-8989 In Silico Study of Bioactive Compounds from Syzygium malaccense Targeting HER2 and Progesterone Receptors in Breast Cancer Nawadhir Fauzan1,2.
Riska Prasetiawati2.
Meilia Suherman2.
Dhania Novitasari1.
Muchtaridi Muchtaridi1* Department of Pharmaceutical Analysis and Medicinal Chemistry.
Faculty of Pharmacy.
Universitas Padjadjaran.
Sumedang.
Indonesia Department of Pharmaceutical Analysis and Medicinal Chemistry.
Faculty of Mathematics and Natural Sciences.
Universitas Garut.
Garut.
Indonesia Abstract Breast cancer remains one of the most common causes of cancer-related deaths among women, with progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER.
being key molecular targets in its progression.
This study aimed to explore the potential of bioactive compounds from Syzygium malaccense that have exhibited anticancer activities, as targeted inhibitors for PR and HER2, using computational approaches.
A total of 155 compounds were initially screened for anticancer potential using the Prediction of Activity Spectra for Substances (PASS), identifying 80 compounds for further analysis.
Druglikeness and pharmacokinetic predictions indicated that several compounds complied with the Rule of Five (RO.
and had favorable absorption and distribution profiles, suggesting their suitability as oral drug candidates.
Molecular docking revealed that quercetin exhibited favorable interactions with PR, particularly involving the Arg 766 residue, while myricetin demonstrated strong binding affinity to HER2, surpassing trastuzumab, and interacting with key residues Asp 863.
Lys 753.
Ala 751, and Leu 796.
Molecular dynamics simulations confirmed the stability of the Myricetin-HER2 complex under physiological conditions over 15 ns, supporting its potential as a HER2 inhibitor.
These findings highlight myricetin and quercetin as promising natural compounds for breast cancer therapy targeting HER2 and PR, respectively.
However, further experimental validation, including in vitro and in vivo studies, is necessary to confirm their therapeutic efficacy and safety.
Overall, this study supports Syzygium malaccense as a valuable source of natural bioactive compounds for breast cancer drug discovery.
Keywords: in silico screening.
Syzygium malaccense, breast cancer, progesterone receptor.
HER2.
Submitted: July 7, 2025 Revised: September 12, 2025 Accepted: September 17, 2025 Corresponding author: muchtaridi@unpad.
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INTRODUCTION
Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide (Bray, et al.
, 2.
Among its molecular subtypes, other than the well-studied estrogen receptor (ER) as biomarker for this cancer type, progesterone receptor-positive (PR ) and human epidermal growth factor receptor 2-positive (HER2 ) breast cancers stand out due to their clinical behavior and therapeutic implications (Yersal & Barutca, 2.
The PR receptor supports tumor growth by mediating hormone-dependent cell proliferation, while HER2, a member of the ErbB receptor family, is frequently amplified in aggressive tumors, driving proliferation through downstream signaling cascades (Hsu & Hung, 2.
Overexpression of HER2 occurs in approximately 15 % of breast cancer cases and is associated with poor clinical outcomes and higher recurrence rates (Zhao, et al.
, 2.
Meanwhile, although PR tumors are often hormone-responsive, resistance to endocrine therapy remains a persistent clinical challenge (Lu, et al.
, 2.
Current treatment strategies for these subtypes, including anti-HER2 monoclonal antibodies, tyrosine kinase inhibitors (TKI.
, and selective hormone modulators, have significantly improved patient survival (Swain, et al.
, 2.
However, treatment failure due to drug resistance and systemic toxicity continues to highlight the need for safer and more effective therapeutic alternatives (Amalia, et al.
, 2.
Natural products, especially those derived from medicinal plants, offer a promising reservoir of bioactive compounds with potential anticancer properties.
Syzygium malaccense, commonly known as Malay apple, is a tropical plant traditionally consumed as fruit and utilized in folk medicine.
Recent studies have shown that its fruit extract possesses antioxidant and cytotoxic activities against various cancer cell lines (Vadu, et al.
, effects largely attributed to its rich content of flavonoids, anthocyanins, and phenolic acids.
Despite these promising findings, the molecular mechanisms underlying the interactions of its bioactive compounds with breast cancer-related targets remain insufficiently understood.
particular, the role of HER2 and PR, both of which play central roles in the pathogenesis and progression of breast cancer, has not been extensively explored in the context of S.
bioactive compounds.
Therefore, this study aims to evaluate the potential interactions of S.
compounds with HER2 and PR, providing an initial assessment of their relevance as breast cancer therapeutic candidates.
Nonetheless, it remains possible that these findings may also uncover meaningful polypharmacological potential in future In silico approaches such as molecular docking and molecular dynamics simulations provide valuable tools to predict and analyze ligand-protein interactions prior to experimental These methods help accelerate drug discovery by identifying promising candidates based on their binding affinity and stability with molecular (Prasetiawati, et al.
, 2.
Hence, this study aimed to investigate the therapeutic efficacy of bioactive compounds extracted from Syzygium malaccense against PR and HER2 breast cancer targets employing an insilico screening methodology.
MATERIALS AND METHODS
Screening of Bioactive Compounds The selection of bioactive compounds from Syzygium malaccense was based on an extensive literature review using the keyword Aubioactive compound of Syzygium malaccenseAy (Batista, et , 2017.
Feltrin, et al.
, 2020.
Ismail, et al.
, 2010.
Karioti, et al.
, 2007.
Nunes, et al.
, 2016.
Pino, et , 2004.
Rajan & Bhat, 2019.
Reis, et al.
, 2021.
Savi, et al.
, 2020.
Tukiran & Putri, 2.
Reported compounds from various scientific articles were then compiled, curated, and verified for their relevance before being incorporated into this study as the compound dataset.
Indonesian Journal of Cancer Chemoprevention.
February 2025 ISSN: 2088Ae0197 e-ISSN: 2355-8989 Prediction of Anticancer Activity Using PASS Online An initial prediction of anti-breast cancer activity of compounds derived from Syzygium malaccense was conducted using the Prediction of Activity Spectra for Substances (PASS Onlin.
web Compounds with a probability of activity value greater than 0.
5 were considered potentially active and selected for further analysis (Filimonov, et al.
, 2.
The analysis focused on key pharmacokinetic parameters, including human intestinal absorption (HIA).
Caco-2 cell permeability, and plasma protein binding (PPB), as well as toxicity-related properties such as mutagenicity and carcinogenicity.
Chemical structures of the compounds were uploaded through the platformAos interface, and the resulting data were analyzed to evaluate the drug-likeness and safety potential of each compound (Dulsat, et al.
, 2.
Molecular Geometry Optimization of Bioactive Compounds The three-dimensional molecular structures of bioactive compounds derived from Syzygium malaccense were subjected to geometry optimization using MarvinSketch software.
The optimization process was performed using the Merck Molecular Force Field (MMFF.
method to obtain the most stable conformations for further analysis.
Target Protein Selection and Preparation The three-dimensional crystal structures of the target proteins were obtained from the Protein Data Bank .
ttps://w.
org/) with PDB ID 1SQN (Mokashi & Bhatia, 2.
for the progesterone receptor and PDB ID 3PP0 (Mutiah, et al.
for the HER2.
Protein-ligand complexes were separated using Discovery Studio VisualizerA.
Both protein and ligand structures were prepared using AutoDock ToolsA, including the removal of water molecules, addition of polar hydrogen atoms, and charge assignment.
The prepared structures were saved in PDBQT format.
Structural validation and binding affinity calculations were performed using AutoDock VinaA.
Drug-Likeness Evaluation Based on LipinskiAos Rule of Five The secondary metabolites of Syzygium malaccense used in this study were retrieved from the PubChem database.
Ligand structures were prepared using MarvinSketch, where energy minimization was performed with the MMFF94 force field and the resulting structures were saved in MOL2 format.
These MOL2 files were then reopened in MarvinSketch, protonated at physiological pH .
, and saved in PDB Following structural preparation, the physicochemical properties of each compound were evaluated using the LipinskiAos Rule of Five via the online tool provided by SCFBio .
ttp://w.
scfbio-iitd.
in/software/drugdesign/lipinski.
to assess their oral drug-likeness potential (Jayaram, et al.
, 2.
Pharmacokinetic and Toxicity Prediction via PreADMET Server The pharmacokinetic and toxicity profiles of selected Syzygium malaccense compounds were predicted using the PreADMET web server .
ttp:// Molecular Docking To ensure the accuracy of the docking protocol, validation was first carried out by re-docking the native ligands into the active sites of the PR and HER2.
Once validated, the main docking simulations were performed using AutoDock VinaA with the same parameters.
The docking results were then visualized and analyzed using Discovery Studio VisualizerA.
The analysis focused on the binding affinity and key amino acid residues that interacted directly with the ligands at the active sites of the target proteins.
Molecular Dynamics Molecular dynamics simulations were performed using the OpenMM toolkit (Eastman, et al.
, 2.
to evaluate the stability of the ligandprotein complex formed between the HER2 Fauzan, et al.
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receptor and the ligand with the lowest binding energy obtained from molecular docking The simulation began with the generation of topologies for both the protein and the The ff19SB force field was used to construct the receptor topology, while the ligand was parameterized using the GAFF2 force field.
The system was solvated using the TIP3P water model.
Following system preparation, equilibration and production phases were carried out for a total simulation time of 15 Subsequent analyses included the evaluation of Root Mean Square Deviation (RMSD).
Root Mean Square Fluctuation (RMSF), and Radius of Gyration (R.
to assess the structural stability and flexibility of the complex throughout the simulation.
RESULTS
Screening of Anti-Breast Cancer Activity A total of 155 bioactive compounds from Syzygium malaccense were identified and selected for this study based on literature screening from previously published scientific journals.
The complete list of these compounds is provided in Supplementary Table S1.
The bioactive compounds of Malay apple were evaluated for their potential anti-breast cancer activity using the PASS Online prediction tool.
Out of 155 compounds, 80 were predicted to possess anti-breast cancer activity based on their probability scores.
This screening aimed to provide an early estimation of each compoundAos pharmacological The PASS Online output includes values for probability of activity (P.
and probability of inactivity (P.
, which represent the likelihood that a given compound exhibits the predicted biological activity.
Compounds with Pa>0.
5 were considered to have significant potential and were selected for further analysis.
The results of the screening are presented in Supplementary Table S2.
LipinskiAos Rule Five Analysis.
Pharmacokinetics and Toxicity The online portal .
ttp://scfbio-iitd.
was used to predict the potential of the tested compounds as oral drugs based on LipinskiAos Rule of Five, which assesses drug-likeness.
According to this rule, optimal oral drugs should have a molecular weight <500 Da.
Log P<5, hydrogen bond donors <5, and hydrogen bond acceptors <10 to ensure good absorption and membrane permeability (Az-Zahra, et al.
, 2.
Table 1 presents a summary of the pharmacokinetic and toxicity profiles of 80 tested compounds.
A total of 64 compounds complied with LipinskiAos Rule of Five (RO.
, while 16 did not.
Pharmacokinetic absorption was further predicted using HIA and Caco2 permeability, while distribution was estimated by Plasma Protein Binding (PPB).
HIA predicts intestinal absorption, with values >70% indicating good absorption (Sagitasa, et al.
, 2.
Caco2 assays estimate membrane permeability, with >70 nm/sec reflecting lipophilic properties (Suherman, et al.
, 2.
PPB
assesses how strongly a compound binds to plasma proteins, with >90% indicating strong binding (Nusantoro & Fadlan, 2.
Toxicity was evaluated using Ames and carcinogenicity predictions.
A positive Ames result suggests potential mutagenicity, while carcinogenicity tests confirm cancer risk (Hartanti, et al.
, 2.
Based on pharmacokinetic parameters, 57 compounds were predicted to have good absorption, 16 with moderate absorption, and 7 with poor absorption.
In terms of distribution, 74 compounds exhibited moderate membrane permeability and 6 compounds showed low Furthermore, 38 compounds were predicted to have strong plasma protein binding (PPB), while 42 exhibited weak binding.
Regarding toxicity profiles, 26 compounds were predicted to be non-mutagenic, 54 mutagenic, 22 carcinogenic, and 58 non-carcinogenic.
Indonesian Journal of Cancer Chemoprevention.
February 2025 ISSN: 2088Ae0197 e-ISSN: 2355-8989 Table 1.
Results of lipinski's rule of five analysis, pharmacokinetics, and toxicity analysis.
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Table 1.
Results of lipinski's rule of five analysis, pharmacokinetics, and toxicity analysis continuous.
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Results of lipinski's rule of five analysis, pharmacokinetics, and toxicity analysis continuous.
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Table 1.
Results of lipinski's rule of five analysis, pharmacokinetics, and toxicity analysis .
Description:
HIA(%):
70-100 is well absorbed (*) 20-70 absorbed enough (**) <20 poorly adsorbed (***) CaCo-2.
>70 high permeability (*) 4-70 medium permeability (**) <4 low permeability (***) Docking Validation Docking parameter validation occurs prior to the docking process for the test ligands.
The docking parameter is considered valid if it can re-docking the native ligand that has been withdrawn from the native ligand or the ligand complex to its original position with an RMSD value less than 2 yI (Astuty & Komari, 2.
The RMSD values obtained from re-docking of native ligands are summarized in Table 2.
The redocking results showed that the progesterone receptor (PDB ID: 1SQN) exhibited an RMSD value of 0.
yI, while the HER2 receptor (PDB ID: 3PP.
demonstrated an RMSD value of 0.
6678 yI.
The RMSD values were declared valid and ready for use in molecular docking simulations of the test Table 2.
Docking validation results.
Grid Center
Grid Box
PDB
RMSD
I) X Y Z
1SQN
3PP0
PPB (%):
>90 tightly bound (*) <90 weakly bound (**) Molecular Docking Simulation Docking validation was performed by redocking the native ligand into the binding site of the receptor.
The redocking results showed an RMSD value of <2 yI (Astuty & Komari, 2.
, which is in accordance with the standard criteria for docking validation and indicates that the applied protocol can reliably reproduce the ligand binding Therefore, the docking parameters used in this study are considered valid, and the predicted ligand-receptor interactions can be regarded as The complete list of these compounds is provided in Supplementary Table S3 and Supplementary Table S4.
The docking of Malay apple compounds on progesterone receptor and HER2, quercetin-PR, and myricetin-HER2 complex was predicted to have the highest binding activity based on the similarity of hydrogen bonds and lower bond free energy values.
Quercetin is bound to essential amino acids of PR in Arg 766, and myricetin is bound to HER2 amino acid residues in Asp 863.
Lys 753.
Ala 751, and Leu 796 (Figure .
The similarity of amino acid residues bound by the test compounds, the native ligand, and the Indonesian Journal of Cancer Chemoprevention.
February 2025 ISSN: 2088Ae0197 e-ISSN: 2355-8989 Figure 1.
The 2-dimentional docking visualization from molecular docking between bioactive compounds in Syzygium malaccense (A) : complex PR-quercetin, (B) : complex HER2- myriceti.
reference compounds indicates that the test compounds are predicted to exhibit comparable pharmacological activity, as these residues constitute an essential part of the receptorAos active site (Mutiah, et al.
, 2.
Molecular docking simulation results can be seen in Table 3.
Molecular Dynamic Simulation Molecular Dynamics (MD) simulations were conducted to assess the stability of ligandAe receptor interactions under physiological conditions (Chairunisa, et al.
, 2.
Since the docking results show stronger binding between myricetin-HER2 compared to the reference drug .
, we then focus on evaluating the binding dynamics between these complexes.
The simulations, performed for 15 ns using OpenMM on Google Colab connected to Google Drive, evaluated the HER2-ligand complexes.
The RMSD analysis showed that myricetin had an average fluctuation 14 yI .
04 yI), higher than the natural ligand O3Q .
62 yI) and the reference ligand Trastuzumab .
92 yI).
All ligands were considered stable with RMSD values below 5 yI (Chairunisa, et al.
, 2.
RMSF analysis indicated that myricetin caused higher fluctuations in several residues (Ala 706 to Asp .
, while stable residues included Val 905.
Trp 913, and Asp 863.
Both O3Q and Trastuzumab showed similar fluctuation patterns, but trastuzumab had Table 3.
Results of molecular docking simulation and analysis of linked amino acid residues.
Receptor
Progesteron
HER2
Compound cal/mo.
Conventional Hydrogen Interaction Native ligand (Norethindron.
Arg 766
Quercetin
Native ligand
(O3Q)
Trastuzumab (Comparative Myricetin Arg 766.
Gln 725.
Asn 719.
Met 756 Asp 863.
Met Asp 863.
Ala 751.
Lys 753.
Leu 796.
Thr Asp 863.
Lys 753.
Met 801.
Ala 751.
Leu Fauzan, et al.
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Figure 2.
Results of molecular dynamics simulation for myricetin and HER2 complex for 15 ns showed (A) RMSD, (B) RMSF, and (C) radius of gyration graphs.
more stable residues, suggesting better overall Radius of Gyration (R.
results demonstrated that all ligands maintained structural stability throughout the simulation, although transient fluctuations were observed for myricetin at 1156 ps.
O3Q at 1313 ps, and trastuzumab at 731 ps, indicating brief conformational changes.
Overall, trastuzumab exhibited greater stability compared to myricetin (Figure .
DISCUSSION
This study provides new insights into the potential of bioactive compounds from Syzygium malaccense as therapeutic agents for breast cancer by targeting progesterone receptor (PR) and HER2, two key molecular targets involved in breast cancer Initial screening using PASS analysis revealed that 80 out of 155 compounds showed potential anticancer activity, indicating that S.
malaccense could be a valuable source of secondary metabolites.
These findings align with previous studies highlighting the therapeutic potential of tropical medicinal plants in cancer drug Drug-likeness analyses revealed that several compounds fulfilled the Rule of Five (RO.
criteria and exhibited favorable absorption and distribution profiles, supporting their potential as oral drug However, these predictions did not cover toxicity, metabolism, or long-term safety aspects, underscoring the need for further validation through in vivo studies.
Consistent with previous reports, natural products often exhibit strong pharmacological activities despite not fully complying with RO5, due to their complex structures and specific interactions with biological Indonesian Journal of Cancer Chemoprevention.
February 2025 ISSN: 2088Ae0197 e-ISSN: 2355-8989 targets (Doak, et al.
, 2.
Therefore, structural optimization of these compounds is recommended to enhance their pharmacokinetic profiles and reduce potential toxicity.
Molecular docking analysis showed that quercetin interacted favorably with PR, particularly at the key residue Arg 766.
Although its binding energy was higher than that of the native ligand, the interaction profile suggests that quercetin may act as a modulator of PR activity.
This finding is in line with previous reports demonstrating the antiproliferative effects of quercetin on hormoneresponsive breast cancer cells (Altundag, et al.
Meanwhile, myricetin exhibited a stronger binding affinity toward HER2, even surpassing the reference ligand trastuzumab.
Its interaction with essential residues such as Asp 863.
Lys 753.
Ala 751, and Leu 796 suggests that myricetin may potentially inhibit HER2 oncogenic activity (Mutiah, et al.
, 2.
The subsequent Molecular Dynamics (MD) simulation confirmed the stability of the myricetin-HER2 complex under physiological conditions for 15 ns, supporting the potential of myricetin as a HER2 inhibitor.
Although the 15 ns simulation provided meaningful insights into the stability of the ligand-receptor complexes, we recognize that longer simulations .
, 50-100 n.
would offer stronger reliability and capture broader conformational changes.
Therefore, extending the MD simulation duration will be an important direction for future studies.
These results are consistent with previous studies showing that flavonoids like myricetin can modulate tyrosine kinase receptor activity.
Nevertheless, the main limitation of this study lies in its reliance on computational approaches without experimental Critical factors such as bioavailability, metabolic stability, and off-target effects require further investigation to confirm the therapeutic efficacy of these compounds.
In this study, trastuzumab was selected as the reference control in the molecular docking and molecular dynamics analyses, considering its established role as a standard clinical therapy for HER2-positive breast cancer.
However, it should be acknowledged that Trastuzumab interacts with the extracellular domain of HER2 rather than the ATP-binding site.
Therefore, although Lapatinib was not directly employed as a comparator, in this study the tested compounds were first compared with the native ligand of HER2 kinase (PDB ID:
3PP.
, which is itself a tyrosine kinase inhibitor.
This allows for the molecular interaction profiles of the compounds to still be evaluated in relation to a mechanistically relevant ATP-binding site inhibitor, thereby minimizing the limitation regarding the absence of a tyrosine kinase inhibitor comparator.
This study has several limitations that should be acknowledged.
First, the use of trastuzumab as a comparator in molecular docking and molecular dynamics analysis is less relevant due to its different mechanism of action compared to ligands binding at the ATP-binding site.
tyrosine kinase inhibitor such as lapatinib would have been more representative.
however, this simulation was not conducted in the present work, thus constituting one of the limitations of the study.
Second, the investigation was restricted to in silico analysis and has not yet been validated through in vitro or in vivo experiments, which will be essential for confirming the findings.
Nevertheless, the current funding support has enabled this study to be carried out as an initial step toward the development of potential HER2 inhibitors.
These findings are expected to provide a foundation for further studies aimed at designing derivatives with enhanced activity against HER2.
Phytochemical investigations have reported that this plant contains considerable amounts of flavonoids, particularly myricetin and quercetin (Arumugam, et al.
, 2019.
Oldoni, et al.
, 2025.
Prasniewski, et al.
, 2.
, which are suggested to contribute to its pharmacological activities.
Based on these findings, future studies are recommended to conduct in vitro and in vivo experiments to Fauzan, et al.
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validate the anticancer activity of myricetin and quercetin, particularly in PR and HER2 breast cancer models.
Pharmacokinetic and toxicological studies in animal models are also needed to assess their safety profiles.
Additionally, chemical structure modification, such as functional group addition or prodrug design, could be explored to enhance their pharmacological properties.
CONCLUSION
Myricetin and quercetin, two bioactive compounds derived from Syzygium malaccense, exhibited promising potential as targeted therapeutic agents against breast cancer.
Myricetin exhibited strong binding affinity toward the HER2 receptor, interacting with key residues Asp 863.
Lys 753.
Ala 751, and Leu 796, and showed stable complex formation during a 15 ns molecular dynamics simulation, suggesting its potential as a HER2 inhibitor.
Quercetin, on the other hand, displayed favorable interactions with the (PR), involving Arg 766, and achieved the best binding energy among the tested ligands, although still lower than the natural ligand.
These findings suggest that myricetin and quercetin could serve as potential candidates for HER2 and PR-targeted breast cancer therapy, respectively.
However, as a future direction, these in silico results should be validated through experimental studies using breast cancer cell lines such as MCF-7 for PR-positive validation and SK-BR-3 or BT-474 for HER2-positive validation, along with cell viability and apoptosis assays to confirm the predicted inhibitory potential.
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