Naphthoquinones from Onosma: Molecular Mechanisms of Action in the Treatment and Prevention of COVID-19

Öz

Absrtact COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected in December 2019 in Wuhan, China. There is currently no effective treatment or immunization for the virus, and it is spreading rapidly with a high mortality rate. As a crucial CoV enzyme involved in initiating both viral replication and transcription, the COVID-19 main protease (Mpro) is an appealing target for researchers. Novel therapeutics are urgently required to treat the early stages of COVID-19 caused by SARS-CoV-2. Therefore, to find potential COVID-19 Mpro inhibitors, naphthoquinones from the Onosma genus were screened to find out their possible effects on the Mpro enzyme. In this study, we employed a range of computational approaches, including molecular docking and MM-GBSA, to uncover potential inhibitors of SARS-CoV-2 Mpro from existing natural product databases. According to our findings, the molecules deoxyshikonin, 3-hydroxy-isovalerylshikonin, propionylshikonin, and acetylshikonin have high binding affinities for the Mpro enzyme. In addition, it was observed that the other shikonin compounds have anti-Mpro enzyme activity. Docking simulations and molecular mechanics suggest that shikonin derivatives might be effective anti-SARS-CoV-2 compounds.

Anahtar Kelimeler

• COVID-19
• Molecular Docking
• Naphthoquinones
• Onosma
• Shikonin

Kaynakça

1. Lillie, P. J., Samson, A., Li, A., Adams, K., Capstick, R., Barlow, G. D., Easom, N., Hamilton, E., Moss, P. J., Evans, A., Ivan, M., Taha, Y., Duncan, C. J. A., & Schmid, M. L., & The Airborne HCID Network, PHE Incident Team. (2020). Novel coronavirus disease (Covid-19): The first two patients in the UK with person to person transmission. Journal of Infection, 80, 578–606. https://doi.org/10.1016/j.jinf.2020.02.020
2. Lai, C. C., Liu, Y. H., Wang, C. Y., Wang, Y. H., Hsueh, S. C., Yen, M. Y., Chien Ko, W., & Hsueh, P. R. (2020). Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths. Journal of Microbiology, Immunology and Infection, 53(3), 404-412. https://doi.org/10.1016/j.jmii.2020.02.012
3. De Wit, E., Van Doremalen, N., Falzarano, D., & Munster, V. J. (2016). SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology, 14(8), 523-534. https://doi.org/10.1038/nrmicro.2016.81
4. Wu, J. T., Leung, K., & Leung, G. M. (2020). Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. The Lancet, 395(10225), 689-697. https://doi.org/10.1016/S0140-6736(20)30260-9
5. Yan, S., Sun, H., Bu, X., & Wan, G. (2020). New strategy for COVID-19: an evolutionary role for RGD motif in SARS-CoV-2 and potential inhibitors for virus infection. Frontiers in Pharmacology, 11, 912. https://doi.org/10.3389/fphar.2020.00912
6. Van Der Hoek, L., Pyrc, K., Jebbink, M. F., Vermeulen-Oost, W., Berkhout, R. J., Wolthers, K. C., & Berkhout, B. (2004). Identification of a new human coronavirus. Nature medicine, 10(4), 368-373. https://doi.org/10.1038/nm1024
7. Zheng, J. (2020). SARS-CoV-2: an emerging coronavirus that causes a global threat. International journal of biological sciences, 16(10), 1678. 10.7150/ijbs.45053
8. Hilgenfeld, R. (2014). From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. The FEBS journal, 281(18), 4085-4096. https://doi.org/10.1111/febs.12936

9. Ortega, J. T., Serrano, M. L., Pujol, F. H., & Rangel, H. R. (2020). Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target. EXCLI journal, 19, 400. http://dx.doi.org/10.17179/excli2020-1189
10. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., & Yang, H. (2020). Structure of M pro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293. https://doi.org/10.1038/s41586-020-2223-y
11. El-Shazly, A., Abdel-Ghani, A., & Wink, M. (2003). Pyrrolizidine alkaloids from Onosma arenaria (Boraginaceae). Biochemical Systematics and Ecology, 31(5), 477-485. https://doi.org/10.1016/S0305-1978(02)00177-1
12. Binzet, R. (2009). Anatomical and palynological investigations on endemic Onosma mersinana Riedl, Binzet & Orcan. Pakistan Journal of Botany, 41, 503-510.
13. Ozgen, U., Miloglu, F. D., & Bulut, G. (2011). Quantitative determination of shikonin derivatives with UV-Vis spectrophotometric methods in the roots of Onosma nigricaule. Reviews in Analytical Chemistry, 30(2), 59-63. https://doi.org/10.1515/revac.2011.014
14. Kagramanyan, N. S., & Mnatsakanyan, V. A. (1985). Shikonin and its derivatives from Onosma setosum roots. Armyanskii Khimicheskii Zhurnal, 38(8), 527-8.
15. Sut, S., Pavela, R., Kolarčik, V., Cappellacci, L., Petrelli, R., Maggi, F., & Benelli, G. (2017). Identification of Onosma visianii roots extract and purified shikonin derivatives as potential acaricidal agents against Tetranychus urticae. Molecules, 22(6), 1002. https://doi.org/10.3390/molecules22061002
16. Ozgen, U., Ikbal, M., Hacimuftuoglu, A., Houghton, P. J., Gocer, F., Dogan, H., & Coskun, M. (2006). Fibroblast growth stimulation by extracts and compounds of Onosma argentatum roots. Journal of ethnopharmacology, 104(1-2), 100-103. https://doi.org/10.1016/j.jep.2005.08.052
17. Schrödinger Release 2020-3: Maestro, Schrödinger, LLC, New York, NY, 2020
18. Kılınç, N. Inhibition profiles and molecular docking studies of antiproliferative agents against aldose reductase enzyme. International Journal of Chemistry and Technology, 5(1), 77-82. https://doi.org/10.32571/ijct.944049
19. Genheden, S.; Ryde, U. (2015) The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opinion on Drug Discovery, 10(5), 449-461. https://doi.org/10.1517/17460441.2015.1032936
20. Oladele, J. O., Ajayi, E. I., Oyeleke, O. M., Oladele, O. T., Olowookere, B. D., Adeniyi, B. M., & Oladiji, A. T. (2020). A systematic review on COVID-19 pandemic with special emphasis on curative potentials of Nigeria based medicinal plants. Heliyon, e04897. https://doi.org/10.1016/j.heliyon.2020.e04897
21. Tada, M., Okuno, K., Chiba, K., Ohnishi, E., & Yoshii, T. (1994). Antiviral diterpenes from Salvia officinalis. Phytochemistry, 35(2), 539-541. https://doi.org/10.1016/S0031-9422(00)94798-8
22. Koch, C., Reichling, J., Kehm, R., Sharaf, M. M., Zentgraf, H., Schneele, J., & Schnitzler, P. (2008). Efficacy of anise oil, dwarf‐pine oil and chamomile oil against thymidine‐kinase‐positive and thymidine‐kinase‐negative herpesviruses. Journal of Pharmacy and Pharmacology, 60(11), 1545-1550. https://doi.org/10.1211/jpp.60.11.0017
23. Mukhtar, M., Arshad, M., Ahmad, M., Pomerantz, R. J., Wigdahl, B., & Parveen, Z. (2008). Antiviral potentials of medicinal plants. Virus research, 131(2), 111-120. https://doi.org/10.1016/j.virusres.2007.09.008
24. Tan, W. C., Jaganath, I. B., Manikam, R., & Sekaran, S. D. (2013). Evaluation of antiviral activities of four local Malaysian Phyllanthus species against herpes simplex viruses and possible antiviral target. International Journal of Medical Sciences, 10(13), 1817. 10.7150/ijms.6902
25. Mikaili, P., Maadirad, S., Moloudizargari, M., Aghajanshakeri, S., & Sarahroodi, S. (2013). Therapeutic uses and pharmacological properties of garlic, shallot, and their biologically active compounds. Iranian journal of basic medical sciences, 16(10), 1031.
26. Theisen, L. L., & Muller, C. P. (2012). EPs® 7630 (Umckaloabo®), an extract from Pelargonium sidoides roots, exerts anti-influenza virus activity in vitro and in vivo. Antiviral research, 94(2), 147-156. https://doi.org/10.1016/j.antiviral.2012.03.006
27. Yu, M. S., Lee, J., Lee, J. M., Kim, Y., Chin, Y. W., Jee, J. G., & Jeong, Y. J. (2012). Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorganic & medicinal chemistry letters, 22(12), 4049-4054. https://doi.org/10.1016/j.bmcl.2012.04.081
28. Zandi, K., Teoh, B. T., Sam, S. S., Wong, P. F., Mustafa, M. R., & AbuBakar, S. (2012). Novel antiviral activity of baicalein against dengue virus. BMC complementary and alternative medicine, 12(1), 1-9. https://doi.org/10.1186/1472-6882-12-214
29. Andújar, I., Ríos, J. L., Giner, R. M., & Recio, M. C. (2013). Pharmacological properties of shikonin–a review of literature since 2002. Planta medica, 79(18), 1685-1697. 10.1055/s-0033-1350934
30. Chen, X., Yang, L., Zhang, N., Turpin, J. A., Buckheit, R. W., Osterling, C., & Howard, O. Z. (2003). Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. Antimicrobial agents and chemotherapy, 47(9), 2810-2816. https://doi.org/10.1128/AAC.47.9.2810-2816.2003