Lecanoric Acid As a Multi-Target Candidate Against Breast Cancer: In Silico Interactions With 17β-HSD1, ERα, EGFR, Bcl-xL and ADMET Profiling

Öz

Aim: Breast cancer is a common disease in women with high morbidity and mortality. Although various treatment modalities are available, chemoresistance remains a major problem in breast cancer. This study aimed to investigate the interactions of lecanoric acid, a natural compound with bioactive properties, with receptors considered therapeutic targets in breast cancer. Materials and Methods: The 3D structures of the target proteins 17β-HSD1 (1FDW), ERα (6CBZ), EGFR (1M17), and Bcl-xL (2W3L) were retrieved from the RCSB Protein Data Bank (RCSB PDB; https://www.rcsb.org) using their PDB IDs. The 3D structure of lecanoric acid was downloaded from the PubChem database and prepared for analysis. AutoDock Vina was used for molecular docking analyses. Ligand-receptor interactions were visualized using Discovery Studio 2021 (BIOVIA, USA). In addition, the physicochemical, medicinal chemistry, pharmacokinetic, and toxicity profiles of lecanoric acid as a drug candidate were comprehensively evaluated using ADMETlab 3.0. Results: Molecular docking analyses indicated that lecanoric acid bound to the target proteins with docking scores ranging from -7.1 to -7.7 kcal/mol. In addition, the probability of P-gp inhibition by lecanoric acid was predicted to be very low, and the radar plot showed that the evaluated ADMET parameters remained within the predefined lower and upper limits. Conclusions: Lecanoric acid was found to exhibit notable binding affinity toward 17β-HSD1, ERα, EGFR, and Bcl-xL, which are of critical importance in breast cancer pathology. Although lecanoric acid appears to have important advantages in terms of its physicochemical, medicinal chemistry, pharmacokinetic, and toxicity profiles, in vitro and in vivo studies are needed to validate its therapeutic potential.

Anahtar Kelimeler

• 17β-HSD1
• ADMET
• breast cancer
• EGFR
• lecanoric acid
• molecular docking

Meme Kanserine Karşı Çok Hedefli Bir Aday Olarak Lekanorik Asit: 17β-HSD1, ERα, EGFR, Bcl-xL ile In Silico Etkileşimler ve ADMET Profillemesi

Öz

Amaç: Meme kanseri kadınlarda sık görülen, morbiditesi ve mortalitesi yüksek bir hastalıktır. Tedavide farklı yöntemler bulunmakla birlikte kemorezistans, meme kanserinde önemli bir problemdir. Bu çalışmada biyoaktif özelliklere sahip doğal bir bileşik olan lekanorik asitin meme kanserinde tedavi hedefi olarak değerlendirilen reseptörlerle etkileşiminin araştırılması amaçlanmıştır. Gereç ve Yöntem: Hedef proteinlerin 3D yapıları, 17β-HSD1 (1FDW), ERα (6CBZ), EGFR (1M17) ve Bcl-xL (2W3L) PDB kimlikleri kullanılarak RCSB Protein Veri Bankası’ndan (RCSB PDB; https://www.rcsb.org) elde edildi. Lekanorik asidin 3D yapısı PubChem veritabanından indirildi ve analizler için hazırlandı. Moleküler docking analizleri için AutoDock Vina kullanıldı. Ligand-reseptör etkileşimleri Discovery Studio 2021 (BIOVIA, ABD) kullanılarak görselleştirildi. Ayrıca lekanorik asidin ilaç adayı olarak fizikokimyasal, tıbbi kimya, farmakokinetik ve toksisite profilleri ADMETlab 3.0 kullanılarak kapsamlı bir şekilde değerlendirildi. Bulgular: Moleküler docking analizlerinde lekanorik asitin hedef proteinlere -7,1 ila -7,7 kcal/mol arasında değişen kenetlenme skorlarıyla bağlandığı belirlenmiştir. Ayrıca lekanorik asidin P-gp inhibisyonu olasılığının çok düşük olduğu ve değerlendirilen ADMET parametrelerinin önceden tanımlanmış alt ve üst sınırlar içinde kaldığı radar grafiğinde kaydedilmiştir. Sonuç: Lekanorik asitin meme kanseri patolojisinde kritik öneme sahip 17β-HSD1, ERα, EGFR, ve Bcl-xL ile dikkate değer bağlanma afinitesi gösterdiği belirlenmiştir. Fizikokimyasal, tıbbi kimya, farmakokinetik ve toksisite profilleri açısından önemli avantajlara sahip olduğu belirlenen lekanorik asitin terapötik potansiyelinin doğrulanması için in vitro ve in vivo çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

• 17β-HSD1
• ADMET
• meme kanseri
• EGFR
• lekanorik asit
• moleküler docking

Kaynakça

1. 1. World Health Organization. Breast cancer. Last accessed date: 26.03.2026. Available from: https://www.who.int/
2. 2. Şimşekli D. Meme kanseri tedavisinde melatoninin etkisi. Ağrı Med J. 2025;3(3):139-146. doi:10.61845/agrimedical.1688576
3. 3. Łukasiewicz S, Czeczelewski M, Forma A, et al. Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers (Basel). 2021;13(17):4287. doi:10.3390/cancers13174287
4. 4. International Agency for Research on Cancer. Breast cancer cases and deaths are projected to rise globally. Last accessed date: 26.03.2026. Available from: https://www.iarc.who.int/news-events/breast-cancer-cases-and-deaths-are-projected-to-rise-globally/
5. 5. Kim J, Harper A, McCormack V, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 2025;31(4):1154-1162. doi:10.1038/s41591-025-03502-3
6. 6. Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: Past, present and future. Semin Cancer Biol. 2018;52(Pt 1):56-73. doi:10.1016/j.semcancer.2017.08.010
7. 7. Burguin A, Diorio C, Durocher F. Breast cancer treatments: Updates and new challenges. J Pers Med. 2021;11(8):808. doi:10.3390/jpm11080808
8. 8. Islam MR, Tayyeb JZ, Paul HK, et al. In silico analysis of potential inhibitors for breast cancer targeting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses. J Cell Mol Med. 2024;28(15):e18584. doi:10.1111/jcmm.18584

9. 9. Xiong X, Zheng LW, Ding Y, et al. Breast cancer: pathogenesis and treatments. Signal Transduct Target Ther. 2025;10(1):49. doi:10.1038/s41392-024-02108-4
10. 10. He W, Gauri M, Li T, et al. Current knowledge of the multifunctional 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1). Gene. 2016;588(1):54-61. doi:10.1016/j.gene.2016.04.031
11. 11. Heinosalo T, Saarinen N, Poutanen M. Role of hydroxysteroid (17beta) dehydrogenase type 1 in reproductive tissues and hormone-dependent diseases. Mol Cell Endocrinol. 2019;489:9-31. doi:10.1016/j.mce.2018.08.004
12. 12. Wu BX, Wu HT, Lan YZ, et al. Targeting estrogen receptor alpha in breast cancer for novel therapies resistance mechanisms and future directions. Discov Oncol. 2025;17(1):204. doi:10.1007/s12672-025-04302-4
13. 13. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-247. doi:10.1146/annurev-med-070909-182917
14. 14. Teklemariam AB, Muche ZT, Agidew MM, et al. Receptor tyrosine kinases and steroid hormone receptors in breast cancer: Review of recentevidences. Metabol Open. 2024;24:100324. doi:10.1016/j.metop.2024.100324
15. 15. Ferrari P, Schiavone ML, Scatena C, et al. Molecular mechanisms and therapeutic strategies to overcome resistance to endocrine therapy and CDK4/6 inhibitors in advanced ER+/HER2- breast cancer. Int J Mol Sci. 2025;26(7):3438. doi:10.3390/ijms26073438
16. 16. Kang L, Guo Y, Zhang X, et al. A positive cross-regulation of HER2 and ER-α36 controls ALDH1 positive breast cancer cells. J Steroid Biochem Mol Biol. 2011;127(3-5):262-268. doi:10.1016/j.jsbmb.2011.08.011
17. 17. Silva JPN, Pinto B, Silva PMA, et al. BCL-2 and BCL-xL in Cancer: Regulation, Function, and Therapeutic Targeting. Int J Mol Sci. 2026;27(2):1123. doi:10.3390/ijms27021123
18. 18. Levitsky DO, Dembitsky VM. Anti-breast Cancer Agents Derived from Plants. Nat Prod Bioprospect, 2014;5(1):1-16. doi: 10.1007/s13659-014-0048-9.
19. 19. Mir MA, Banik BK. Sustainable healing: Natural compounds facilitating the future cancer treatment. World Dev. Sustain. 2025;6,100215. doi:10.1016/j.wds.2025.100215
20. 20. Burul F, Altunlu Ö, Ferah Okkay I, et al. Investigation of the antitumoral activity of syringic acid on HT-29 cells: An in vitro study. RTPharma, 2023;1(3):123-130. https://izlik.org/JA94ZN37LD
21. 21. Liao MJ, Dong HY, Chen G, et al. Mechanisms and advantages of natural derived small molecule compounds in the prevention and treatment of colorectal cancer: a review. Front Pharmacol. 2025;16:1658493. doi:10.3389/fphar.2025.1658493
22. 22. Zhang X, Fei G, Xiujia S, et al. Natural compound-nanoparticle therapies for breast cancer: A review from 2018-2025. Phytomedicine. 2026;150:157652. doi:10.1016/j.phymed.2025.157652
23. 23. Luo H., Yamamoto Y., A Kim J. et al. Lecanoric acid, a secondary lichen substance with antioxidant properties from Umbilicaria antarctica in maritime Antarctica (King George Island). Polar Biol 2009;32:1033–1040. doi:10.1007/s00300-009-0602-9
24. 24. Roser LA, Erkoc P, Ingelfinger R, et al. Lecanoric acid mediates anti-proliferative effects by an M phase arrest in colon cancer cells. Biomed Pharmacother. 2022;148:112734. doi:10.1016/j.biopha.2022.112734
25. 25. Sezen S, Burul F. Lecanoric acid shows strong binding interactions with ALS-related SOD1, TDP-43, and TBK1: an in silico approach. Van Yuzuncu Yıl University 4th International Health Sciences Congress; 2026: 156–160.
26. 26. Saha S., Ray R, Paul S. In vitro screening and in silico docking analysis identifies two novel compound lecanoric acid and atranorin from parmotrema tinctorum, exhibiting potent anti-hepatocarcinoma activity. Biointerface Res Appl Chem, 2023;13(6):507. doi:10.33263/BRIAC136.507
27. 27. Moeller G, Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol. 2009;301(1-2):7-19. doi:10.1016/j.mce.2008.10.040
28. 28. Anandan S, Gowtham HG, Shivakumara CS, et al. Integrated approach for studying bioactive compounds from Cladosporium spp. against estrogen receptor alpha as breast cancer drug target. Sci Rep. 2022;12(1):22446. doi:10.1038/s41598-022-22038-x
29. 29. Gowtham HG, Ahmed F, Anandan S, et al. In Silico Computational Studies of Bioactive Secondary Metabolites from Wedelia trilobata against Anti-Apoptotic B-Cell Lymphoma-2 (Bcl-2) Protein Associated with Cancer Cell Survival and Resistance. Molecules. 2023;28(4):1588. Published 2023 Feb 7. doi:10.3390/molecules28041588
30. 30. Asli F, Bensahbane I. Molecular docking study: Application to the epidermal growth factor receptor. Chemistry Proceedings. 2024; 16(1):82. doi:10.3390/ecsoc-28-20219
31. 31. Sezen S, Ozakar RS, Bayram C, et al. A Plantago lanceolata L. extract-based cream enhances wound healing by modulating inflammatory mediators and growth factors in a full-thickness wound model: In vivo and İn-silico evidence. J. Drug Deliv. Sci. Technol., 2026;107635. doi:10.1016/j.jddst.2025.107635
32. 32. Xia J, Hu JN, Wang Z, et al. Based on network pharmacology and molecular docking to explore the protective effect of Epimedii Folium extract on cisplatin-induced intestinal injury in mice. Front Pharmacol. 2022;13:1040504. doi:10.3389/fphar.2022.1040504
33. 33. Sezen S, Karadayi M, Yesilyurt F, et al. Acyclovir provides protection against 6-OHDA-induced neurotoxicity in SH-SY5Y cells through the kynurenine pathway. Neurotoxicology. 2025;106:1-9. doi:10.1016/j.neuro.2024.11.005
34. 34. Li X, Xue T, Zhang P, et al. Predict potential pharmacological mechanisms of Ling-gui-Zhu-gan Decoction in treating unstable angina pectoris using liquid chromatography-mass spectrometry and network pharmacology. Front Chem. 2025;13:1649538. doi:10.3389/fchem.2025.1649538
35. 35. Fu L, Shi S, Yi J, et al. ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support. Nucleic Acids Res. 2024;52(W1):W422-W431. doi:10.1093/nar/gkae236
36. 36. Sezen S, Burul F. A drug repositioning approach: Antidiabetic empagliflozin may be a potential drug for the treatment of ALS. RTPharma, 2026a;3(3):87-97. doi:10.62425/rtpharma.1828403
37. 37. Zhang J, Wu Y, Li Y, et al. Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism. Phytomedicine. 2024;129:155600. doi:10.1016/j.phymed.2024.155600
38. 38. Poirier D, Roy J, Maltais R. A targeted-covalent inhibitor of 17β-HSD1 blocks two estrogen-biosynthesis pathways: In vitro (metabolism) and ın vivo (xenograft) studies in T-47D breast cancer models. Cancers (Basel). 2021;13(8):1841. doi:10.3390/cancers13081841
39. 39. M Rafeeq M. Molecular docking analysis of phytochemicals with estrogen receptor alpha. Bioinformation. 2022;18(8):697-702. doi:10.6026/97320630018697
40. 40. Alkhathlan HZ, Alshareef E, Dutta T, et al. Unlocking the therapeutic potential of Origanum majorana through GC-MS and computational analysis to identify EGFR inhibitors for breast cancer. Sci Rep. Published online March 3, 2026. doi:10.1038/s41598-026-41138-6
41. 41. Kawiak A, Kostecka A. Regulation of Bcl-2 family proteins in estrogen receptor-positive breast cancer and their ımplications in endocrine therapy. Cancers (Basel). 2022;14(2):279. doi:10.3390/cancers14020279
42. 42. Sachdeva A, Dhawan D, Jain GK, et al. Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer. Cancers (Basel). 2022;15(1):268. doi:10.3390/cancers15010268
43. 43. Dewhirst MW, Secomb TW. Transport of drugs from blood vessels to tumour tissue. Nat Rev Cancer. 2017;17(12):738-750. doi:10.1038/nrc.2017.93
44. 44. Lee J, Beers JL, Geffert RM, et al. A Review of CYP-mediated drug ınteractions: Mechanisms and ın vitro drug-drug ınteraction assessment. Biomolecules. 2024;14(1):99. doi:10.3390/biom14010099
45. 45. U.S. Food and Drug Administration. ABRAXANE™ for injectable suspension (paclitaxel protein-bound particles for injectable suspension). Last accessed date: 26.03.2026. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf
46. 46. Kapagan T, Bulut N, Erdem GU. Polypharmacy and drug-drug interactions in metastatic breast cancer patients receiving cyclin-dependent kinase (CDK) 4/6 inhibitors. J Oncol Pharm Pract. 2024;30(8):1403-1410. doi:10.1177/10781552231218959
47. 47. Basak D, Arrighi S, Darwiche Y, et al. Comparison of anticancer drug toxicities: Paradigm shift in adverse effect profile. Life (Basel). 2021;12(1):48. doi:10.3390/life12010048