Araştırma Makalesi

DOI :10.26650/IstanbulJPharm.2025.1070319 IUP :10.26650/IstanbulJPharm.2025.1070319 Tam Metin (PDF)

Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species

Fadıl Kaan Kuran, Ebru Didem Kuran, Mahmut Miski

Background and Aims: Due to the high mortality and morbidity rates associated with cancer, it is crucial to advance research in this area to develop new and effective agents. Natural product chemistry plays a crucial role in identifying potential lead molecules for the treatment of various cancers. Recently, several studies have demonstrated the selective and potent cytotoxic activity of sesquiterpene coumarins isolated from Ferula species against various cancer cell lines. In this study, we aimed to utilize in silico molecular docking studies to demonstrate the potential of sesquiterpene coumarins as inhibitors of Bcl xL. For this purpose, 35 sesquiterpene coumarins were collected based on previous studies.

Methods: Molecular docking studies were conducted to examine the interactions of cytotoxic sesquiter pene coumarins with the active site of the Bcl-xL enzyme, using advanced computational techniques. Additionally, ADME (Absorption, Distribution, Metabolism, and Excretion) studies were performed to predict the pharmacokinetic properties and drug-likeness of sesquiterpene coumarins, ensuring their potential as viable therapeutic agents.

Results: As a result of this study, straight-chain sesquiterpene coumarin-derived compounds were more effectively positioned within the active site of the Bcl-xL enzyme and formed hydrogen bonds with amino acids. ADME analysis revealed favourable pharmacokinetic profiles, supporting their potential use in drug development.

Conclusion: These findings revealed promising Bcl-xL inhibitory activities of umbelliprene-type sesquiter pene derivatives, which might be a starting point for further structural optimisation to acquire novel compounds exhibiting more potent Bcl-xL inhibitory activity, paving the way for new therapeutic approaches in cancer treatment.

Anahtar Kelimeler: Bcl-xL, cancer, Ferula, molecular docking, sesquiterpene coumarins

Referanslar

Ali-Shtayeh, M.S., Jamous, R.M., Salameh, N.M.Y., Jamous, R.M., & Hamadeh, A.M.A. (2016). Complementary and alternative medicine use among cancer patients in Palestine with special reference to safety-related concerns. Journal of Ethnopharmacology, 187, 104-122. https://doi.org/10.1016/j.jep.2016.04.038. google scholar
Barthomeuf, C., Demeule, M., Grassi, J., Saidkhodjaev, A., & Beliveau, R. (2006). Con-ferone from Ferula schtschurowskiana enhances vinblastine cytotoxicity in MDCK-MDR1 cells by competitively inhibiting P-glycoprotein transport. Planta Med,, 72, 634-639. DOI: 10.1055/s-2006-931574. google scholar
Czabotar, P.E., Lessene, G., Strasser, A., & Adams, J.M. (2014). Control of apoptosis by the BCL-2 protein Family: implications for physiology and therapy. Nat. Rev. Mol, Cell Biol,, 15, 49-63. https://doi.org/10.1038/nrm3722. google scholar
Dastan, D., Salehi, P., Gohari, A.R., Ebrahimi, S.N., Aliahmadi, A., & Hamburger, M. (2014). Bioactive sesquiterpene coumarins from Ferula pseudalliacea. Planta Med,, 80, 1118-1123. DOI: 10.1055/s-0034-1382996. google scholar
Ece., A., & Sevin, F. (2010). Exploring QSAR on 4-Cyclohexylmethoxypyrimidines as antitumor agents for their inhibitory activity of CDK2. Letters in Drug Design & Discovery, 7, 625-631. https://doi.org/10.2174/157018010792929612. google scholar
Eisenman, S.W., Zaurov, D.E., & Struwe, L. (2013). Medicinal Plants of Central Asia: Uzbekistan and Kyrgyzstan. Springer: New York, NY, USA. google scholar
Eruçar, F.M., Kuran, F.K., Altıparmak-Ülbegi, G., Özbey, S., Karavuş, Ş.N., Arcan, G.G., Yazıcı-Tütüniş, S., Tan, N., Aksoy-Sağırlı, P., & Miski, M. (2023a). Sesquiterpene coumarin ethers with selective cytotoxic activities from the roots of Ferula huber-morathii Peşmen (Apiaceae) and unequivocal determination of the absolute stereochemistry of samarcandin. Pharmaceuticals, 16, 792. https:// doi.org/10.3390/ph16060792. google scholar
Eruçar, F.M., Senadeera, S.P.D., Wilson, J.A., Goncharova, E., Beutler, J.A., & Miski, M. (2023b). Novel cytotoxic sesquiterpene coumarin ethers and sulfur-containing compounds from the roots of Ferula turcica. Molecules, 28, 5733. https://doi. org/10.3390/molecules28155733. google scholar
Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shelley, M., Perry, J.K., Shaw, D.E., Francis, P., & Shenkin, P.S. (2004). Glide: A new approach for rapid, accurate docking and scoring. 1. Method and Assessment of Docking Accuracy. Journal of Medicinal Chemistry, 47(7), 1739-1749. https://doi.org/10.1021/jm0306430. google scholar
Friesner, R.A., Murphy, R.B., Repasky, M.P., Frye, L.L., Greenwood, J.R., Halgren, T.A., Sanschagrin, P.C., & Mainz, D.T. (2006). Extra Precision Glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. Journal of Medicinal Chemistry, 49(21), 6177-6196. https://doi.org/ 10.1021/jm051256o. google scholar
Gholami, O., Jeddi-Tehrani, M., Iranshahi, M., Zarnani, A.H., & Ziai, S.A. (2013). Umbelliprenin from Ferula szowitsiana Activates both Intrinsic and Extrinsic Pathways of Apoptosis in Jurkat T-CLL Cell Line. Iranian Journal of Pharmaceu-tical Reserach. 12(3): 371-376. google scholar
Gunther, R.T. (1968) The Greek Herbal of Dioscorides, 3rd ed.. Hafner Publishing Company: London, UK. google scholar
Halgren, T.A., Murphy, R.B., Friesner, R.A., Beard, H.S., Frye, L.L., Pollard, W.T., & Banks, J.L. (2004). Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment Factors in Database Screening. Journal of Medicinal Chemistry, 47(7), 1750-1759. https://doi.org/10.1021/jm030644s. google scholar
Iranshahy, M., Farhadi, F., Paknejad, B., Zareian, P., Iranshahi, M., Karami, M., & Abtahi, S.R. (2019). Gummosin, a sesquiterpene coumarin from Ferula assa-foetida is preferentially cytotoxic to human breast and prostate cancer cell lines. Avicenna Journal of Phytomedicine, 9(5), 446-453. google scholar
Iranshahy, M., & Iranshahi, M. (2011). Traditional uses, phytochemistry and pharma-cology of asafoetida (Ferula assa-foetida oleo-gum-resin) - A review. Journal of Ethnopharmacology, 134, 1-10. https://doi.org/10.1016/j.jep.2010.11.067. google scholar
Kamoldinov, K., Li, J., Eshbakova, K., Sagdullaev, S., Xu, G., Zhou, Y., Li, J., & Aisa, H.A. (2021). Sesquiterpene coumarins from Ferula samarkandica Korovin and their bioactivity. Phytochemistry, 187, 112705. https://doi.org/10.1016/j.phytochem. 2021.112705. google scholar
Kasaian, J., Mosaffa, F., Behravan, J., Masullo, M., Piacente, S., Ghandadi, M., & Iran-shahi, M. (2015). Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins, Fitoterapia, 103, 149-154. https://doi.org/10.1016/j.fitote.2015.03.025. google scholar
Kirkin, V., Joos, S., & Zörnig, M. (2004). The role of Bcl-2 family members in tumori-genesis. Biochimica et Biophysica Acta 1644(2-3), 229-249. https://doi.org/10. 1016/j.bbamcr.2003.08.009. google scholar
Korovin, E.P. (1947) Generis Ferula (Tourn.) L. Monographia illustrate; Academiae Scientiarum URSS. Tashkent, Uzbekistan. google scholar
Li, G., Wang, J., Li, X., Cao, L., Lv, N., Chen, G., Zhu, J., & Si, J. (2015a). Two new sesquiterpene coumarins from the seeds of Ferula sinkiangensis. Phytochem-istry letters, 13, 123-126. https://doi.org/10.1016/j.phytol.2015.06.002. google scholar
Li, G., Li, X., Cao, L., Zhang, L., Shen, L., Zhu, J., Wang, J., & Si, J. (2015b). Sesquiter-pene coumarins from seeds of Ferula sinkiangensis. Fitoterapia, 103, 222-226. https://doi.org/10.1016/j.fitote.2015.03.022. google scholar
Li, G.Z., Wang, J.C., Li, X.J., Cao, L., Gao, L., Lv, N., & Si, J.Y. (2016). An unusual sesquiter-pene coumarin from the seeds of Ferula sinkiangensis. Journal of Asian Natural Products Research, 18(9), 891-896. https://doi.org/10.1080/10286020. 2016.1168813. google scholar
Lipinski, C.A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods, 44(1), 235-249. https://doi.org/10.1016/S1056-8719(00)00107-6. google scholar
Lipinski, C.A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337-341. https://doi.org/10.1016/j. ddtec.2004.11.007. google scholar
Meng, H., Li, G., Huang, J., Zheng, K., Wang, H., & Wang, J. (2013). Sesquiterpene coumarin and sesquiterpene chromone derivatives from Ferula ferulaeoides (Steud.) Korov. Fitoterapia, 86, 70-77. https://doi.org/10.1016/j.fitote.2013.02.002. google scholar
Mohammadhosseini, M., Venditti, A., Sarker, S.D., Nahar, L., & Akbarzadeh, A. (2019). The genus Ferula: Ethnobotany, phytochemistry and bioactivities - A review. Industrial Crops & Products, 129, 350-394. https://doi.org/10.1016/j.indcrop. 2018.12.012. google scholar
Plants of the World Online (POWO), Ferula L. Available online: https://powo.science. kew.org/taxon/30105171-2#publications. (accessed on 29.05.2024). google scholar
Pimenov, M.G., & Leonov, M.V. (1993). The Genera of the Umbelliferae: Royal Botanic Gardens. London, UK. google scholar
Sarkar, S., Horn, G., Moulton, K., Oza, A., Byler, S., Kokolus, S., & Longacre, M. (2013). Cancer development, progression, and therapy: an epigenetic overview. Inter-national Journal of Molecular Sciences, 14(10), 21087-21113. https://doi.org/10. 3390/ijms141021087. google scholar
Sastry, G.M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design, 27, 221-234. https:// doi.org/10.1007/s10822-013-9644-8. google scholar
Shomirzoeva, O., Xu, M.Y., Sun, Z.J., Li, C., Nasriddinov, A., Muhidinov, Z., Zhang, K., Gu, Q., & Xu, J. (2021). Chemical constituents of Ferula seravschanica. Fitoterapia, 149, 104829. https://doi.org/10.1016/j.fitote.2021.104829. google scholar
Tao, Z., Wang, X., Chen, J., Ingram, J.P., Jin, S., Judge, R.A., Kovar, P.J., Park, C., Sun, C., Wakefield, B.D., Zhou, L., Zhang, H., Elmore, S.W., Phillips, D.C., Judd, A.S., Lever-son, J.D., & Souers, A.J. (2021). Structure-Based Design of A-1293102, a Potentand Selective BCL-Xl Inhibitor. Medicinal Chemistry Letters, 12(6), 1011-1016. https:// doi.org/10.1021/acsmedchemlett.1c00162. google scholar
Tosun, F., Beutler, J.A., Ransom, T.T., Miski, M. (2019). Anatolicin, a highly potent and se-lective cytotoxic sesquiterpene coumarin from the root extract of Heptaptera anatolica. Molecules, 24(6), 1153. https://doi.org/10.3390/molecules24061153. google scholar
Wang, J.L., Sang, C.Y., Wang, J., Li, P.L., Chai, T., Naghavi, M.R., Zhao, Y.M., & Yang, J.L. (2023a). Sesquiterpene coumarins from Ferula sinkiangensis and their anti-pancreatic cancer effects. Phytochemistry, 214, 113824. https://doi.org/10.1016/ j.phytochem.2023.113824. google scholar
Wang, J., Wang, H., Zhang, M., Li, X., Zhao, Y., Chen, G., Si, J., & Jiang, L. (2020). Sesquiter-pene coumarins from Ferula sinkiangensis K.M.Shen and their cytotoxic activities. Phytochemistry, 180, 112531. https://doi.org/10.1016/j.phytochem. 2020.112531. google scholar
Wang, J., Zheng, Q., Wang, H., Shi, L., Wang, G., Zhao, Y., Fan, C., & Si, J. (2023b). Sesquiterpenes and sesquiterpene derivatives from Ferula: Their chemical structures, biosynthetic pathways, and biological properties. Antioxidants, 13(1), 7. https://doi.org/10.3390/antiox13010007. google scholar
Yapasert, R., Sripanidkulchai, B., Teerachaisakul, M., Banchuen, K., & Banjerdpongchai, R. (2020). Anticancer effects of a traditional Thai herbal recipe Benja Amarit extracts against human hepatocellular carcinoma and colon cancer cell by targeting apoptosis pathways. Journal of Ethnopharmacology, 254, 112732. https://doi.org/10.1016/j.jep.2020.112732. google scholar
Zhang, M.M., Kamoldinov, K., Nueraihemaiti, M., Turdu, G., Zou, G.A., & Aisa, H.A. (2024). Sesquiterpene coumarins with anti-vitiligo and cytotoxic activities from Fer-ula samarkandica. Phytochemistry Letters, 61, 21-28. https://doi.org/10.1016/j. phytol.2024.03.004. google scholar
Zhang, L., Si, J., Li, G., Li, X., Zhang, L., Gao, L., Huo, X., Liu, D., Sun, X., & Cao, L. (2015). Umbelliprenin and lariciresinol isolated from a long-term-used herb medi-cine Ferula sinkiangensis induce apoptosis and G0/G1 arresting in gastric cancer cells. RCS Advances, 5, 91006-91017. google scholar

Atıflar

Biçimlendirilmiş bir atıfı kopyalayıp yapıştırın veya seçtiğiniz biçimde dışa aktarmak için seçeneklerden birini kullanın

DIŞA AKTAR

APA

Kuran, F.K., Kuran, E.D., & Miski, M. (2020). Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species. İstanbul Journal of Pharmacy, 0(0), -. https://doi.org/10.26650/IstanbulJPharm.2025.1070319

AMA

Kuran F K, Kuran E D, Miski M. Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species. İstanbul Journal of Pharmacy. 2020;0(0):-. https://doi.org/10.26650/IstanbulJPharm.2025.1070319

ABNT

Kuran, F.K.; Kuran, E.D.; Miski, M. Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species. İstanbul Journal of Pharmacy, [Publisher Location], v. 0, n. 0, p. -, 2020.

Chicago: Author-Date Style

Kuran, Fadıl Kaan, and Ebru Didem Kuran and Mahmut Miski. 2020. “Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species.” İstanbul Journal of Pharmacy 0, no. 0: -. https://doi.org/10.26650/IstanbulJPharm.2025.1070319

Chicago: Humanities Style

Kuran, Fadıl Kaan, and Ebru Didem Kuran and Mahmut Miski. “Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species.” İstanbul Journal of Pharmacy 0, no. 0 (Mar. 2025): -. https://doi.org/10.26650/IstanbulJPharm.2025.1070319

Harvard: Australian Style

Kuran, FK & Kuran, ED & Miski, M 2020, 'Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species', İstanbul Journal of Pharmacy, vol. 0, no. 0, pp. -, viewed 14 Mar. 2025, https://doi.org/10.26650/IstanbulJPharm.2025.1070319

Harvard: Author-Date Style

Kuran, F.K. and Kuran, E.D. and Miski, M. (2020) ‘Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species’, İstanbul Journal of Pharmacy, 0(0), pp. -. https://doi.org/10.26650/IstanbulJPharm.2025.1070319 (14 Mar. 2025).

MLA

Kuran, Fadıl Kaan, and Ebru Didem Kuran and Mahmut Miski. “Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species.” İstanbul Journal of Pharmacy, vol. 0, no. 0, 2020, pp. -. [Database Container], https://doi.org/10.26650/IstanbulJPharm.2025.1070319

Vancouver

Kuran FK, Kuran ED, Miski M. Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species. İstanbul Journal of Pharmacy [Internet]. 14 Mar. 2025 [cited 14 Mar. 2025];0(0):-. Available from: https://doi.org/10.26650/IstanbulJPharm.2025.1070319 doi: 10.26650/IstanbulJPharm.2025.1070319

ISNAD

Kuran, FadılKaan - Kuran, EbruDidem - Miski, Mahmut. “Molecular docking approach to identify Bcl-xL inhibitory effect of sesquiterpene coumarins of Ferula species”. İstanbul Journal of Pharmacy 0/0 (Mar. 2025): -. https://doi.org/10.26650/IstanbulJPharm.2025.1070319

ZAMAN ÇİZELGESİ

Gönderim	04.06.2024
Kabul	18.07.2024
Çevrimiçi Yayınlanma	19.02.2025

LİSANS

Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.

İstanbul Journal of Pharmacy