In Silico Studies of Carotenoid Antioxidants in Sand Lobster (Panulirus homarus) as Candidate Anti-Breast Cancer Compounds
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Abstract
Breast cancer is the most diagnosed and deadliest type of cancer among women worldwide. In Indonesia, breast cancer ranks as the most prevalent and deadly cancers, with 58,256 cases and 22,692 deaths. This research aims to analyze the potential of carotenoid antioxidants found in the sand lobster (Panulirus homarus) as breast cancer treatment candidates through an in silico approach. In this study, six carotenoid compounds were evaluated: dinoxanthin, diadinoxanthin, zeaxanthin, lutein, astaxanthin, and violaxanthin, using 4-hydroxytamoxifen, genistein, and exemestane as standard ligands, and tamoxifen, metformin, and letrozole as positive controls. The 3D crystal protein structures used for molecular docking were obtained from the Protein Data Bank (PDB), including estrogen receptor alpha (PDB ID: 3ERT), estrogen receptor beta (PDB ID: 1X7J), and aromatase (PDB ID: 3S7S) as target receptors. Subsequently, bioactivity and bioavailability analyses of the test compounds were performed. Proteins and test compounds were prepared, followed by molecular docking against the estrogen receptor alpha, estrogen receptor beta, and aromatase, with visualization performed using Discovery Studio. Molecular dynamics simulations were performed to evaluate the stability of binding interactions. Toxicity prediction was carried out using the Protox Web Server (https://tox-new.charite.de/protox_II/). The in silico results indicate that two of the six tested compounds, lutein and violaxanthin, showed favorable predicted binding interactions with estrogen receptor alpha, estrogen receptor beta, and aromatase. Additionally, in silico toxicity predictions indicated favorable toxicity profiles for these compounds, suggesting their potential as candidates for further investigation against breast cancer.
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References
International Agency for Research on Cancer (IARC). Indonesia - Global Cancer Observatory [Internet]. Globocan; 2022 [cited 2024 August 25]. Available from: https://gco.iarc.who.int/media/globocan/factsheets/populations/360-indonesia-factsheet.pdf
Sun Y, Zhang X, Li J, Wang L. The histological and morphological characteristics of breast tissue. J Anat Physiol. 2020;227(3):212-8.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.
Massardi NA. The role of estrogen in the development of breast cancer. Biomed J Indonesia. 2021;7(2):231-41.
Yin L, Duan JJ, Bian XW, Yu SC. Triplenegative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020;22(1):1-13.
Klinge CM. Estrogenic effects on the cardiovascular system and the role of estrogen receptors. Int J Mol Sci. 2019;20(15):3722.
Miziak P, Baran M, Błaszczak E, Przybyszewska-Podstawka A, Kałafut J, Smok-Kalwat J, Dmoszyńska-Graniczka M, Kiełbus M, Stepulak A. Estrogen receptor signalling in breast cancer. Cancers. 2023;15(19):4689.
Rej RK, Roy J, Allu S. Therapies for the treatment of advanced/metastatic estrogen receptor-positive breast cancer: current situation and future directions. Cancers. 2024;16:552.
Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Implantation, embryogenesis, and placental development. In: Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY, editors. Williams Obstetrics. 23rd ed. New York: The McGraw-Hill Companies; 2010. p. 564.
Mohtar K, Fatimawali F, Rumondor EM, Datu OS, Tallei TE. Studi in silico senyawa eugenol cengkeh (Syzygium aromaticum L.) terhadap reseptor ER-α, ER-β dan HER-2 pada kanker payudara. Pharmacon. 2021;10(3):1001-8.
Ikhtiarudin I, Dona R, Frimayanti N, Utami R, Susianti N, Septama AW. Sintesis, karakterisasi struktur, dan kajian molecular docking senyawa turunan 4'-metoksi flavonol sebagai antagonis reseptor estrogen pada kanker payudara. J Ris Kim. 2022;13(2):236-48.
Maguire O, Pollock JA, Ivanova MM. Dual roles of estrogen receptor α in breast cancer: transcriptional regulation and nongenomic functions. Front Endocrinol. 2019;10:331.
Kim KH, Kim H. Role of estrogen receptor β in breast cancer: from biological understanding to clinical trials. J Mammary Gland Biol Neoplasia. 2020;25(4):235-44.
Zhao H, Zhou L, Shangguan AJ, Bulun SE. Aromatase expression in breast cancer: evidence of intra-tumoral heterogeneity. J Steroid Biochem Mol Biol. 2020;202:105735.
Tarannum J, Manaswini P, Deekshitha C, Gaju RK, Sunder AS. Medical reproductive factors and breast cancer risk. 2019;6(2):40-4.
Zhang X, Spiegelman D, Baglietto L, Bernstein L, Boggs DA, Van Den Brandt PA, Julie E, Gapstur SM, Giles GG, Giovannucci E, Goodman G, Hankinson SE, Helzlsouer KJ, Horn-Ross PL, Inoue M, Jung S, Khudyakov P, Larsson SC, Lof M, Walter C. Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a pooled analysis of 18 prospective cohort studies. Cancer Epidemiol Biomarkers Prev. 2012;21(5):1021-31.
Tanaka T, Shnimizu M, Moriwaki H. Cancer chemoprevention by carotenoids. Molecules. 2012;17(3):3202-42.
Ngginak J, Jubhar CM, Ferdy SR. The identification of carotenoids and testing of carotenoid antioxidants from sand lobster (Panulirus homarus) egg extract. J Mar Biol Aquacult. 2017;2(3):45-53.
Filimonov DA, Druzhilovskiy DS, Lagunin AA, Gloriozova TA, Rudik AV, Dmitriev AV, Pogodin PV, Poroikov VV. Prediction of the biological activity spectra of organic compounds using the PASS Online web resource. Chem Heterocycl Compd. 2014;50(3):444-57.
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.
Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337-41.
O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J Cheminform. 2011;3:33.
Rahmadini A, Tasya I, Lestari WY, Kadir NA, Saputri M, Erika F, Rijai L. Sintesis, molecular docking dan aktivitas sitotoksik senyawa analog kalkon berbasis alfa tetralone terhadap sel kanker payudara MCF-7: Synthesis, molecular docking, and cytotoxic activity of alpha tetralone based chalcone analogue compounds against MCF-7 breast cancer cells. J Sains Kesehatan. 2024;6(1):149-57.
Huey R, Morris GM, Forli S. Using AutoDock 4 and AutoDock Vina with AutoDockTools: A tutorial. Scripps Res Inst Mol. 2012;32.
Singgih M, Benny P, Selvira AIM, Anna Y. Studi in silico metabolit sekunder kapang Monascus sp. sebagai kandidat obat antikolesterol dan antikanker. Universitas Sebelas Maret; 2019. p. 1-25.
Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules. 2015;20(7):13384-421.
Land H, Humble MS. YASARA: a tool to obtain structural guidance in biocatalytic investigations. In: Protein engineering: methods and protocols. p. 43-67; 2018.
Kesuma D, Purwanto BT, Hardjono S. Uji in silico aktivitas sitotoksik dan toksisitas senyawa turunan N-(benzoil)-N’-feniltiourea sebagai calon obat antikanker. J Pharm Sci Clin Res. 2018;3(1):1-11.
Antonius Y, Kharisma VD, Widyananda MH, Yudhana A, Pangestu RP, Widodo S. Prediction of aflatoxin-B1 (AFB1) molecular mechanism network and interaction to oncoproteins growth factor in hepatocellular carcinoma. J Pure Applied Microbiology. 2022;16(3):1844-54.
Lumachi F, Brunello A, Maruzzo M, Basso U, Basso SMM. Treatment of estrogen receptor-positive breast cancer. Curr Med Chem. 2019;26(14):2482-92.
Tjubaryat A, Mastutik G, Bangun H. Inhibitory effect of letrozole compared to other aromatase inhibitors. J Oncol Res Treat. 2019;1(1):1-5.
Doak BC, Kihlberg J. Drug discovery beyond the rule of 5 - Opportunities and challenges. Expert Opin Drug Discov. 2017;12(2):115-9.
Wellek W, Zielke T. Structural stability and potential energy in nanomaterials synthesis. J Comput Chem. 2021;42(10):1567-83.
Cramer CJ. Essentials of computational chemistry: theories and models. 3rd ed. John Wiley & Sons, Ltd; 2020. p. 284.
Sherman W, Beard HS, Farid R. Use of an induced fit receptor structure in virtual screening. Chem Biol Drug Design. 2006;67:83-4.
Spassov DS. Binding affinity determination in drug design: insights from lock and key, induced fit, conformational selection, and inhibitor trapping models. Int J Mol Science. 2024;25(13):7124.
Sliwoski G, Kothiwale S, Meiler J, Lowe EW. Computational methods in drug discovery. Pharmacological Review. 2014;66(1):334-95.
Wang J, Bhattarai A, Do HN, Miao Y. Challenges and frontiers of computational modeling of biomolecular recognition. QRB Discov. 2022;3:e13.
Saputri KE, Fakhmi N, Kusumaningtyas E, Priyatama D, Santoso B. Docking molekular potensi anti diabetes melitus tipe 2 turunan zerumbon sebagai inhibitor aldosa reduktase dengan Autodock-Vina. Chimica et Natura Acta. 2016;14(1):16-20.
Todeschini R, Consonni V. Molecular descriptors for chemoinformatics. The Royal Society of Chemistry; 2019. p. 118.
Cheng T, Li Q, Zhou Z, Wang Y, Bryant SH. Structure-based virtual screening for drug discovery: a problem-centric review. AAPS Journal. 2012;14(1):133-41.
Haider MK. Computational analyses of protein-ligand interaction. University ofYork; 2010. Available from: https://etheses.whiterose.ac.uk/1242/2/the sis_final_mkh_updated.pdf
Pace CN, Fu H, Fryar KL, Landua J, Trevino SR, Shirley BA, Hendricks MM, Iimura S, Gajiwala K, Scholtz JM, Grimsley GR. Contribution of hydrophobic interactions to protein stability. J Molecular Biology. 2011;408(3):514-28.
Al Mughram MH, Catalano C, Herrington NB, Safo M, Kellog G. 3D interaction homology: The hydrophobic residues alanine, isoleucine, leucine, proline, and valine play different structural roles in soluble and membrane proteins. Front Mol Biosci. 2023;10:1116868.
Gong X, Smith JR, Swanson HM, Rubin LP. Carotenoid lutein selectively inhibits breast cancer cell growth and potentiates the effect of chemotherapeutic agents through ROS-mediated mechanisms. Molecules. 2018;23(4):905.
Pernicova I, Korbonits M. Metforminmode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2019;10(3):143-56.
Moldasheva A, Zhakupova A, Aljofan M. Antiproliferative mechanisms of metformin in breast cancer: A systematic review of the literature. Int J Mol Sci. 2025;26(1):247. doi:10.3390/ijms26010247.
Kairys V, Baranauskiene L, Kazlauskiene M, Matulis D, Kazlauskas E. Binding affinity in drug design: Experimental and computational techniques. Expert Opin Drug Discovery. 2019;14(9):841-51.
Arwansyah, Hasrianti. Simulasi Molecular Docking Senyawa Kurkumin dan Analognya Sebagai Selective Androgen Receptor Modulators (SARMs) Pada Kanker Prostat. J Dinamika. 2014;5(2):60-75.
Shen L, Fleming KG. Hydrogen bond stabilizes lipid-accessible polar residues in membrane proteins. Biophys J. 2023;123(3):301a-302a.
Durell SR, Ben-Naim A. Hydrophobichydrophilic forces in protein folding. Biopolymers. 2017;107(8):e23020.
Melnikov S, Mailliot J, Rigger L, Neuner S, Shin B‐S, Yusupova G, Dever TE, Micura R, Yusupov M. Molecular insights into protein synthesis with proline residues. EMBO Reports. 2016;17(12):1776-84.
Pasquet V, Morisset P, Ihammouine S, Chépied A, Aumailley L, Bérard JB, et al. Antiproliferative activity of violaxanthin isolated from bioguided fractionation of Dunaliella tertiolecta extracts. Mar Drugs. 2011;9(5):819-31.
Kastritis PL, Bonvin AMJJ. On the binding affinity of macromolecular interactions: daring to ask why proteins interact. J R Soc Interface. 2013;10(79):20120835.
Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: A powerful approach for structure-based drug discovery. CurrComput Aided Drug Design. 2011;7(2):146-57.
Ferenczy GG, Kellermayer M. Contribution of hydrophobic interactions to protein mechanical stability. Computational Structure Biotechnology Journal. 2022;20:1946-56.
Patil R, Das S, Stanley A, Yadav L, Sudhakar A, Varma AK. Optimized hydrophobic interactions and hydrogen bonding at the target ligand interface lead the pathways of drug-designing. PLoS One. 2010;5(8):e12029.
Karas LJ, Wu CH, Das R, Wu JIC. Hydrogen bond design principles. Wiley Interdisciplinary Reviews: Computational Molecular Science. 2020;10(6):e1477.
Okada AK, Teranishi K, Ambroso MR, Isas JM, Vazquez-Sarandeses E, Lee J-Y, Melo AA, Pandey P, Merken D, Berndt L, Lammers M, Daumke O, Chang K, Haworth IS. Lysine acetylation regulates the interaction between proteins and membranes. Nature Communications. 2021;12(1):1-16.
Kumar P, Li H. In silico techniques for the design and discovery of novel anticancer peptides. Computational Biology Chemistry. 2017;71:215-25.
Elengoe A, Abu Naser M, Hamdan S. Modeling and docking studies on novel mutants (K71L and T204V) of the ATPase domain of human heat shock 70 kDa protein 1. Int Journal Molecular Science. 2014;15(4):6797.
Sapundzhi F, Slavov V. RMSD calculations and computer modeling of protein structures. J Chem Technology Metallurgy. 2020;55(5):935-8.
Blundell TL, Johnson LN. Protein Crystallography. International Journal Molecular Science. 2019;20(21):5286.
Zou Q, Wang Z. Flexible regions in proteins: Exploring their role using RMSF analysis. Proteins: Structur Function Bioinformatics. 2019;87(1):30-42.
Laio A, Parrinello M. Assessing and improving the reliability of molecular dynamics simulations. J Chemical Theory Computational. 2015;11(9):3955-64.
Nag A, Dasgupta A, Sengupta S, Lai TK, Acharya K. An in-silico pharmacophorebased molecular docking study to evaluate the inhibitory potentials of novel fungal triterpenoid Astrakurkurone analogs against a hypothetical mutated main protease of SARS-CoV-2 virus. Computers in Biology and Medicine. 2023;152:106433.
Saraswat J, Riaz U, Patel R. In-silico study for the screening and preparing ionic liquid-AVDs conjugate to combat COVID-19 surge. Journal of Molecular Liquids. 2022;359:119277.
Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018;46(W1):W257-63.
Aziz E, Batool R, Akhtar W, Rehman S, Shahzad T, Malik A, et al. Xanthophyll: Health benefits and therapeutic insights. Life Sci. 2020;240:117104. doi:10.1016/j.lfs.2019.117104.
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Castenmiller J, de Henauw S, Hirsch-Ernst KI, Kearney J, Maciuk A, et al. Safety of astaxanthin for its use as a novel food in food supplements. EFSA J. 2020;18(2):e05993.
