In silico studies concerning the cytotoxic potential and the inhibition of cytochrome P450 of some bioactive compounds present in Asphodeline lutea root extracts

Abstract

Background and Aims: The roots of Asphodeline lutea are traditionally consumed in the diet of people from Mediterranean countries. The methanol root extracts of A. lutea have been proven to possess cytotoxic activity against the MCF-7 and MCF-10A cell lines. The goal of our investigation was to determine the physicochemical and pharmacokinetic properties, possible inhibition against CYP450 isoenzymes, and probable cytotoxic effect of some bioactive components isolated from A. lutea roots using in silico methods. Methods: The Absorption, distribution, metabolism, and excretion (ADME) profiles were determined using the freely available SwissADME server. To increase the robustness of the SwissADME results, further calculations with the QikProp module in Maestro were carried out. The docking studies were carried out with Glide. The Induced-fit docking (IFD) and Molecular Mechanics-Generalized Born Surface Area (MM/ GBSA) modules in Maestro were applied for recalculations. The anticancer activities were predicted by the online server CLC-Pred. Results: The in silico ADME studies identified chrysophanol and helminthosporin as suitable for future evaluations considering their optimal pharmacokinetic profiles. The former compounds adhere to all of Lipinski’s rule of five for drug likeness. The docking studies identified helminthosporin as a potential inhibitor of CYP1A2 and a weak CYP3A4 inhibitor. Chrysophanol, helminthosporin, asphodelin and 10, 7'-bichrysophanol are expected to manifest a strong cytotoxic effect against A2780cisR cell line. They exerted a strong to modest cytotoxic effect against HOP-18, RCC4 and M19-MEL cell lines. 1,5,8-trihydroxy-3- methylanthraquinone exhibited modest action against GIST430 cell line, while 10, 7'-bichrysophanol had moderate activity against A2780 and SW1990 cell lines. Conclusion: Our findings justify the future in vitro and in vivo studies of A. lutea plant extracts as potential anticancer agents.

Keywords

• Asphodeline lutea
• Cytotoxicity
• In silico
• Molecular docking

References

1. Angelov, B., Mateev,E., Georgieva, M., Tzankova, V., & Kondeva-Burdina, M. (2022). İn vitre effects and in silice analYsis of newlY sYnthetized pYrrole derivatives on the activitY of different isoforms of CYtochrome P450: CYP1A2, CYP2D6 and CYP3A4. Pharmacia, 69 (4), 1013-1017. https://doi.org/10.3897/pharmacia. 69.e96626 google scholar
2. Appiah-Opong, R., de Esch, I., Commandeur, J. N. M., Andarini, M., & Vermeulen, Nico P. E. (2008). Structure-activitY relationships for the inhibition of recom-binant human cYtochromes P450 bY curcumin analogues. Eurepean Jeurnal ef Medicinal Chemistry, 43(8), 1621-1631. https://www.sciencedirect.com/science/ article/pii/S0223523407004291 google scholar
3. Atanasov, A.G., Zotchev, S.B., Dirsch, V.M., Orhan, I. E., Banach, M., Rollinger, J. M., Barreca, D., Weckwerth, W., Bauer, R., BaYer, E. A., Majeed, M., BishaYee, A., Bochkov, V., Bonn, G. K., BraidY, N., Bucar, F., Cifuentes, A., D’Onofrio, G., Bodkin, M.,....., & Supuran, C. T. (2021). Natural products in drug discoveıy: advances and opportunities. Nature Reviews Drug Discoveıy, 20, 200-216. https://doi.org/10.1038/s41573-020-00114-z google scholar
4. Bonomo, S., Jprgensen, F.S., & Olsen L. (2017). Dissecting the CYtochrome P450 1A2-and 3A4-mediated metabolism of aflatoxin B1 in ligand and protein contri-butions. Chemistry - A European Journal, 23(12), 2884-2893. https://doi.org/10. 1002/chem.201605094 google scholar
5. Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistrY friendliness of small molecules. Scientific Reports, 7, 42717. https://doi.org/10.3390/10.1038/ srep42717 google scholar
6. Dulsat, J., Lopez-Nieto, B., Estrada-Tejedor, R., & Borrell, J. I. (2023). Evaluation of free online ADMET tools for academic or small biotech environments. Molecules (Basel, Switzerland), 28(2), 776. https://doi.org/10.3390/molecules28020776 google scholar
7. Durân-lturbide, N. A., Dıaz-Eufracio, B. I., & Medina-Franco, J. L. (2020). İn silice ADME/ Tox profiling of natural products: a focus on BIOFACQUIM. ACS Omega, 5(26), 16076-16084. https://doi.org/10.1021/acsomega.0c01581 google scholar
8. Ekroos, M., & Sjögren, T. (2006). Structural basis for ligand promiscuitY in cy-tochrome P450 3A4. Proceedings of the National Academy of Sciences of the United States of America, 103(37), 13682-13687. https://doi.org/10.1073/pnas. 0603236103 google scholar

9. Kim, D-H., Kim, K-H., Kim, D., Jung , H-Ch., Pan, J-G., Chi, Y-T., Ahn, T., & Yun Ch-H. (2010). Oxidation of human cytochrome P450 1A2 substrates by Bacillus megaterium cYtochrome P450 BM3. Journal of Molecular Catalysis B: Enzymatic, 63, 179-187. https://doi.org/10.1016/j.molcatb.2010.01.017. google scholar
10. Kivistö, KT., Kroemer, HK., & Eichelbaum M. (1995). The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug inter-actions. British Journal of Clinical Pharmacology, 40(6), 523-30. doi: 10.1111/ j.1365-2125.1995.tb05796.x. google scholar
11. Lagunin, A. A., Dubovskaja, V. I., Rudik, A. V., Pogodin, P. V., Druzhilovskiy, D. S., Glorio-zova, T. A., Filimonov, D. A., SastrY, N. G., & Poroikov, V. V. (2018). CLC-Pred: A freely available web-service for in silico prediction of human cell line cYtotoxicitY for drug-like compounds. PLOS one, 13(1), e0191838. https://doi.org/10.1371/ journal.pone.0191838 google scholar
12. Lahlou, M. (2013). The success of natural products in drug discoverY. Pharmacology & Pharmacy, 4, 17-31. https://doi.org/10.4236/pp.2013.43A003. google scholar
13. Lazarova, I., Zengin, G., Aktumsek, A., Gevrenova, R., CeYlan, R., & UYsal, S. (2014). HPLC-DAD analYsis of phenolic compounds and antioxidant properties of As-phodeline lutea roots from Bulgaria and TurkeY. İndustrial Crops and Products, 61, 438-441. https://doi.org/10.1016/j.indcrop.2014.07.044. google scholar
14. Lazarova, I., Zengin, G., Bender, O., Zheleva-Dimitrova, D., UYsal, S., CeYlan, R., Gevren-ova, R., Aktumsek, A., Acar, M., & Gunduz, M. (2015). A comparative studY of Bulgarian and Turkish Asphodeline lutea root extracts: HPLC-UV profiles, enzYme inhibitorY potentials and anti-proliferative activities against MCF-7 and MCF-10A cell lines. Journal of Functional Foods, 15, 254-263. https://doi. org/10.1016/j.jff.2015.03.032 google scholar
15. Liu, R., Lyu, X., Batt, S. M., Hsu, M. H., Harbut, M. B., Vilcheze, C., Cheng, B., AjaYİ, K., Yang, B., Yang, Y., Guo, H., Lin, C., Gan, F., Wang, C., Franzblau, S. G., Jacobs, W. R., Jr, Besra, G. S., Johnson, E. F., Petrassi, M., Chatterjee, A. K., . Wang, F. (2017). Determinants of the Inhibition of DprE1 and CYP2C9 bY Antitubercular Thiophenes. Angewandte Chemie (İnternational ed, in English), 56(42), 1301113015. https://doi.org/10.1002/anie.201707324 google scholar
16. Majumder, R., Kanta Das, Ch., & Mandal M. (2019). Lead bioactive compounds of Aloe vera as potential anticancer agent. Pharmacological Research, 148, 104416. https://doi.org/10.1016/j.phrs.2019.104416 google scholar
17. Malik, M. S., Alsantali, R. I., Jassas, R. S., Alsimaree, A. A., SYed, R., Alsharif, M. A., Kalpana, K., Morad, M., Althagafi, I. I., & Ahmed, S. A. (2021). JourneY of anthraquinones as anticancer agents - a sYstematic review of recent literature. RSC Advances, 11(57), 35806-35827. https://doi.org/10.1039/d1ra05686g google scholar
18. Mateev, E., Balkanska-Mitkova, A., Peikova, L., Dimitrova, M., & Kondeva-Burdina, M. (2022). İn vitro and in silico inhibition performance of choline against CYP1A2, CYP2D6 and CYP3A4. Biotechnology & Biotechnological Equipment, 36(1), 925932. https://doi.org/10.1080/13102818.2022.2144452 google scholar
19. Marechal, J.D., Yu, J., Brown, S., Kapelioukh, I., Rankin, E.M., Wolf, C.R., & Sutcliffe, M.J. (2006). İn silico and in vitro screening for inhibition of cYtochrome p450 cYp3a4 bY comedications commonlY used bY patients with cancer. Drug Metabolism and Disposition, 34(4), 534-538. https://doi.org/10.1124/dmd.105.007625. google scholar
20. Pajouhesh, H., & Lenz, GR. (2005). Medicinal chemical properties of successful cen-tral nervous sYstem drugs. NeuroRx,, 2(4), 541-553. https://link.springer.com/ article/10.1602/neurorx.2.4.541 google scholar
21. Ridhwan, M.J.M., Bakar, S.I A., Latip, N.Ab., Ghani, N. Ab. I., & Nor Hadiani, A. (2022). Comprehensive analYsis of human CYP3A4 crYstal structures as a potential tool for molecular docking-based site of metabolism and enzYme inhibition studies. Journal of Computational Biophysics and Chemistry, 21(3), 259-285. https://doi.org/10.1142/S2737416522300012 google scholar
22. Sansen, S., Yano, J. K., ReYnald, R. L., Schoch, G. A., Griffin, K. J., Stout, C. D., & Johnson, E. F. (2007). Adaptations for the oxidation of polYcYclic aromatic hYdrocarbons exhibited bY the structure of human P450 1A2. The Journal of Biological Chemistry, 282(19), 14348-14355. https://doi.org/10.1074/jbc.M611692200 google scholar
23. Sun, D., Gao, W., Hu, H., & Zhou, S. (2022). WhY 90% of clinical drug development fails and how to improve it?. Acta Pharmaceutica Sinica, 12(7), 3049-3062. https:// doi.org/10.1016/j.apsb.2022.02.002 google scholar
24. Tikhomirov, A. S., Shtil, A. A., & Shchekotikhin, A. E. (2018). Advances in the Discovery of Anthraquinone-Based Anticancer Agents. Recent Patents on Anti-cancer Drug Discovery, 13(2), 159-183. https://doi.org/10.2174/1574892813666171206123114 google scholar
25. Tilaoui, M., Mouse., H. A., & ZYad, A. (2021). Update and new insights on future cancer drug candidates from plant-based alkaloids. Frontiers in Pharmacology, 12, 1-19. https://doi.org/10.3389/fphar.2021.719694 google scholar
26. Todorova, G., Lazarova, I., Mikhova, B., & Kostova, I. (2010). Anthraquinone, naphtha-lene and naphthaquinone components of Asphodeline lutea. Chemistry of Natural Compounds,, 46(2), 322-323. https://doi.org/10.1007/s10600-010-9604-7 google scholar
27. Wang, E., Sun, H., Wang, J., Wang, Z., Liu, H., Zhang, J. Z. H., & Hou T. (2019). End-point binding free energy calculation with MM/PBSA and MM/GBSA: strategies and applications in drug design. Chemical Reviews,, 119(16), 9478-9508. https://doi. org/ 10.1021/acs.chemrev.9b00055. google scholar
28. YuenYongsawad, S., Bunluepuech, K.,Wattanapiromsakul, C., & Tewtrakul, S. (2014). Anti-cancer activitY of compounds from Cassia garrettiana heartwood. Songk-lanakarin Journal of Science and Technology, 36, 189-194. https://www. thaiscience.info/Journals/Article/SONG/10968296.pdf google scholar
29. Yim, S. K., Kim, K., Chun, S., Oh, T., Jung, W., Jung, K., & Yun, C. H. (2020). Screening of human CYP1A2 and CYP3A4 inhibitors from seaweed in silico and in vitro. Marine Drugs, 18(12), 603-618. https://doi.org/10.3390/md18120603 google scholar