Design and Computational Analysis of 2-Chlorobenzoylated Quercetin Derivatives as Inhibitors of Estrogen Receptor Alpha

Dwi Utami; Muhammad Fauzi; Laela Hayu Nurani; Any Guntarti; Citra Ariani Edityaningrum; Sugiyanto Sugiyanto; Lalu Muhammad Irham; Mustofa Ahda; Fara Azzahra; Arif Budi Setianto

doi:10.22146/ijc.111483

Design and Computational Analysis of 2-Chlorobenzoylated Quercetin Derivatives as Inhibitors of Estrogen Receptor Alpha

https://doi.org/10.22146/ijc.111483

Dwi Utami^(1*), Muhammad Fauzi⁽²⁾, Laela Hayu Nurani⁽³⁾, Any Guntarti⁽⁴⁾, Citra Ariani Edityaningrum⁽⁵⁾, Sugiyanto Sugiyanto⁽⁶⁾, Lalu Muhammad Irham⁽⁷⁾, Mustofa Ahda⁽⁸⁾, Fara Azzahra⁽⁹⁾, Arif Budi Setianto⁽¹⁰⁾

(1) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(2) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia; Faculty of Pharmacy, Universitas Islam Kalimantan Muhammad Arsyad Al Banjari Banjarmasin, Jl. Adhyaksa, Banjarmasin 70122, Indonesia
(3) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(4) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(5) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(6) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(7) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(8) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(9) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia; Diploma of Pharmacy, Akademi Farmasi Indonesia Yogyakarta, Jl. Veteran, Gg. Jambu, Pandeyan, Umbulharjo, Yogyakarta 55161, Indonesia
(10) Faculty of Pharmacy, Universitas Ahmad Dahlan, Jl. Prof. Dr. Soepomo, Janturan, Yogyakarta 55164, Indonesia
(*) Corresponding Author

Abstract

Breast cancer remains a leading cause of mortality in women, highlighting the need for novel therapeutics. Quercetin, a natural flavonoid, shows anticancer potential but suffers from poor pharmacokinetics. To enhance its activity, 23 quercetin derivatives were designed as the flavonoid derivatives (FLD) series and evaluated using an integrated in silico workflow, including Lipinski’s rule-of-five assessment, molecular docking against the estrogen receptor alpha (ERα; PDB ID: 3ERT), and ADMET prediction. Based on docking scores and favorable ADMET profiles, FLD-4, FLD-5, and FLD-6 were selected for 100 ns molecular dynamics simulations. FLD-4 exhibited the highest stability with an average RMSD of approximately 0.30 nm, while FLD-6 showed larger fluctuations (0.45 nm). SASA analysis revealed more compact structures for FLD-4 and the control ligand (131–133 nm²) compared to quercetin and FLD-6. RMSF analysis confirmed reduced terminal residue flexibility for FLD-4 and FLD-5 (< 0.9 nm), whereas quercetin and FLD-6 fluctuated > 1.0 nm. MM-PBSA analysis further identified FLD-4 as the most stable complex (−205.409 ± 17.844 kJ/mol). Collectively, these results indicate that FLD-4 forms a stable, compact complex with improved binding affinity and drug-likeness, supporting its potential as a lead compound for flavonoid-based breast cancer therapy.

Keywords

quercetin derivatives; breast cancer; estrogen receptor alpha; molecular docking; ADMET; molecular dynamics; MM-PBSA

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References

[1] Ferlay, J., Colombet, M., Soerjomataram, I., Parkin, D.M., Piñeros, M., Znaor, A., and Bray, F., 2021, Cancer statistics for the year 2020: An overview, Int. J. Cancer, 149 (4), 778–789.

[2] Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., and Jemal, A., 2024, Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: Cancer J. Clin., 74 (3), 229–263.

[3] Osborne, A., Adnani, Q.E.S., and Ahinkorah, B.O., 2025, Breast cancer incidence in Indonesia: A sex-disaggregated analysis using WHO health equity assessment toolkit data, BMC Cancer, 25 (1), 986.

[4] Wu, Z.Y., Qiu, K.Y., Gai, Y.J., Wu, J.H., Zhou, B.X., and Shi, Q.F., 2025, Quercetin: A natural ally in combating breast cancer, Int. J. Nanomed., 20, 9155–9177.

[5] Frenț, O.D., Stefan, L., Morgovan, C.M., Duteanu, N., Dejeu, I.L., Marian, E., Vicaș, L., and Manole, F., 2024, A systematic review: Quercetin—secondary metabolite of the flavonol class, with multiple health benefits and low bioavailability, Int. J. Mol. Sci., 25 (22), 12091.

[6] Alizadeh, S.R., and Ebrahimzadeh, M.A., 2022, O-substituted quercetin derivatives: Structural classification, drug design, development, and biological activities, A review, J. Mol. Struct., 1254, 132392.

[7] Khater, M., Watson, K.A., Boateng, S.Y., Greco, F., and Osborn, H.M.I., 2022, Halogenated flavonoid derivatives display antiangiogenic activity, Molecules, 27 (15), 4757.

[8] Fauzi, M., Nurani, L.H., Utami, D., And Irham, L.M., 2025, Quercetin: Synthesis trends, chemical reactions, and its role as an estrogen receptor alpha modulator in breast cancer therapy: A systematic literature review, Trends Sci., 22 (8), 9423.

[9] Ahda, M., Ahmed, Q.U., Utami, D., Mahfudh, N., Syahputra, R., Anwar, M., Hernawan, H., Hanifah, D., Fithri, H.H.Z., Bin Abdul Hamid, A.A., Rofiee, M.S., Jaswir, I., Khatib, A., and Uddin, A.H., 2025, Orthosiphon aristatus leaf extracts as α-glucosidase and soybean lipoxygenase inhibitors and their toxicity: In-vitro and in-silico approaches, Rev. Bras. Farmacogn., 35 (6), 1468–1482.

[10] Roney, M., and Mohd Aluwi, M.F.F., 2024, The importance of in-silico studies in drug discovery, Intell. Pharm., 2 (4), 578–579.

[11] Ayoub, N., Pietrancosta, N., Gianetto, Q.G., Karimova, G., Gedeon, A., and Munier-Lehmann, H., 2026, Exploring the multi-protein assembly of the enzymes of the de novo purine nucleotide biosynthetic pathway from Pseudomonas aeruginosa, Int. J. Biol. Macromol., 343, 149706.

[12] Schrödinger LLC, 2015, The Pymol Molecular Graphics System, Version 1.8.

[13] Daina, A., Michielin, O., and Zoete, V., 2017, SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci. Rep., 7 (1), 42717.

[14] Abraham, M.J., Murtola, T., Schulz, R., Páll, S., Smith, J.C., Hess, B., and Lindahl, E., 2015, GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX, 1-2, 19–25.

[15] Latifa, N., Rais, I.R., Prasasti, D., and Utami, D., 2024, Potential cervical anticancer activity of tomcat beetle (Paederus fuscipes) compounds against estrogen alpha receptor (3ert): In silico study, BIO Web Conf., 148, 04013.

[16] Essa, A.F., Teleb, M., El-Kersh, D.M., El Gendy, A.E.N.G., Elshamy, A.I., and Farag, M.A., 2023, Natural acylated flavonoids: Their chemistry and biological merits in context to molecular docking studies, Phytochem. Rev., 22 (6), 1469–1508.

[17] Terefe, E.M., and Ghosh, A., 2022, Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of phytochemicals isolated from Croton dichogamus against the HIV-1 reverse transcriptase, Bioinf. Biol. Insights, 16, 11779322221125604.

[18] Lo, S., Leung, E., Fedrizzi, B., and Barker, D., 2021, Synthesis, antiproliferative activity and radical scavenging ability of 5-O-acyl derivatives of quercetin, Molecules, 26 (6), 1608.

[19] Yeni, Y., and Rachmania, R.A., 2022, The prediction of pharmacokinetic properties of compounds in Hemigraphis alternata (Burm.F.) T. Ander leaves using pkCSM, Indones. J. Chem., 22 (4), 1081–1089.

[20] Asghar, S., Hameed, S., Al-Masoudi, N.A., Saeed, B., and Shtaiwi, A., 2024, Design, synthesis, docking studies and molecular dynamics simulation of new 1,3,5-triazine derivatives as anticancer agents selectively targeting pancreatic adenocarcinoma (Capan-1), Chem. Biodiversity, 21 (5), e202400112.

[21] Nurisyah, N., Ramadhan, D.S.F., Dewi, R., Asikin, A., Daswi, D.R., Adam, A., Chaerunnimah, C., Sunarto, S., Rafika, R., Artati, A., and Fakih, T.M., 2024, Targeting EGFR allosteric site with marine-natural products of Clathria sp.: A computational approach, Curr. Res. Struct. Biol., 7, 100125.

[22] Rajesh, G.D., Apte, K., Abhirami, P.V., Anusha, S., Ranjitha, A., Kumar, S.B., Sarvottam, K., and Kumar, P., 2025, Comprehensive in silico analysis of flavonoids in breast cancer using molecular docking, ADME, and molecular dynamics simulation approach, Pept. Sci., 117 (1), E24391.

[23] Wang, W., Sun, C., Mao, L., Ma, P., Liu, F., Yang, J., and Gao, Y., 2016, The biological activities, chemical stability, metabolism and delivery systems of quercetin: A review, Trends Food Sci. Technol., 56, 21–38.

[24] Sim, J., Kim, D., Kim, B., Choi, J., and Lee, J., 2025, Recent advances in AI-driven protein–ligand interaction predictions, Curr. Opin. Struct. Biol., 80, 102589.

[25] Safna Hussan, K.P., Davis, A., Lekshmi, S., Shahin Thayyil, M., Chathrattil Raghavamenon, A., and Devassy Babu, T., 2024, Evaluation of the binding efficacy of flavonol derivatives on estrogen receptors (ER) with respect to ring B hydroxylation, Results Chem., 7, 101544.

[26] Lee, S., and Barron, M.G., 2017, Structure-based understanding of binding affinity and mode of estrogen receptor α agonists and antagonists, PloS One, 12 (1), E0169607

[27] Sultan, R., Ahmed, A., Wei, L., Saeed, H., Islam, M., and Ishaq, M., 2023, The anticancer potential of chemical constituents of Moringa oleifera targeting CDK-2 inhibition in estrogen receptor positive breast cancer using in-silico and in vitro approches, BMC Complement. Med. Ther., 23 (1), 396.

[28] Shaw, S., Chourasia, M., Nayak, R., Kumeria, T., Ghosh, M.P., Santoshi, S., and Bose, S., 2025, Molecular interaction of quercetin and its derivatives against nucleolin in breast cancer: In-silico and in-vitro study, J. Biomol. Struct. Dyn., 43 (14), 7348–7359.

[29] Parihar, A., Puranik, N., Nadda, A.K., Kumar, V., Lee, K.W., Kumar, R., Khandia, R., And Khan, R., 2024, Phytochemicals for breast cancer therapeutic intervention: Exploratory in silico molecular docking study, Medinformatics, 0 (0), 1–15.

DOI: https://doi.org/10.22146/ijc.111483