Natural phenolic compounds from Satureja L. as inhibitors of COVID-19 protease (Mpro): Computational investigations

Coronavirus (SARS-CoV-2) causes a new type of severe acute respiratory syndrome that first appeared in Wuhan in December 2019; it is a very fast-spreading and deadly virus. Therefore, urgent discovery or development of “lead compounds” against this virus is crucial. Natural compounds have always served as a great source, especially the use of traditional medicinal plants, in modern drug discovery. This study aimed to investigate the SARS-CoV-2 protease inhibition potential of the phenolic compounds in the genus Satureja L. The affinities of the chosen natural products were understood using molecular docking simulation against the SARS-CoV-2 protease enzyme. The study proved that three different phenolic compounds namely 5,6-dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-7,8-dimethoxy-4H-chromen-4-one, 2-(3,4-dimethoxyphenyl)-5,6-dihydroxy-7,8-dimethoxy-4H-chromen-4-one, and 5,6-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-7,8-dimethoxy-4H-chromen-4-one obtained from Satureja L. taxa were found as promising against SARS-CoV-2 main protease.

Keywords:

Satureja L. Phenolic compounds, COVID-19, Protease inhibitor (Mpro),

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Abad, M.J., Bermejo, P., Gonzales, E., Iglesias, I., Irurzun, A., Carrasco, L., 1999. Antiviral activity of Bolivian plant extracts. General Pharmacology: The Vascular System, 32(4), 499-503.
Abdollahi, M., Salehnia, A., Mortazavi, S.H.R., Ebrahimi, M., Shafiee, A., Fouladian, F., Kazemi, A., 2003. Antioxidant, antidiabetic, anti-hyperlipidemic, reproduction stimulatory properties and safety of essential oil of Satureja khuzestanica in rat in vivo: a toxicopharmacological study. Medical Science Monitor, 9(9), BR331-BR335.
Amanlou, M., Dadkhah, F., Salehnia, A., Farsam, H., Dehpour, A.R., 2005. An anti-inflammatory and anti-nociceptive effects of hydroalcoholic extract of Satureja khuzistanica Jamzad extract. Journal of Pharmaceutical Sciences, 8(1), 102-106.
Askun, T., Tekwu, E.M., Satil, F., Modanlioglu, S., Aydeniz, H., 2013. Preliminary antimycobacterial study on selected Turkish plants (Lamiaceae) against Mycobacterium tuberculosis and search for some phenolic constituents. BMC Complementary and Alternative Medicine, 13(1), 1-11.
Barnes, J., Anderson, L.A., Phillipson, J.D., 2007. Herbal Medicines: a guide for healthcare professionals. London: Pharmaceutical Press.
Başoğlu, F., Ulusoy‐Güzeldemirci, N., Akalın‐Çiftçi, G., Çetinkaya, S., Ece, A., 2021. Novel imidazo [2, 1‐b] thiazole‐based anticancer agents as potential focal adhesion kinase inhibitors: synthesis, in silico, and in vitro evaluation. Chemical Biology & Drug Design, 98(2), 270-282
Bekut, M., Brkić, S., Kladar, N., Dragović, G., Gavarić, N., Božin, B., 2018. Potential of selected Lamiaceae plants in anti (retro) viral therapy. Pharmacological Research, 133, 301-314.
Cetojevic-Simin, D.D., Bogdanovic, G.M., Cvetkovic, D.D., Velicanski, A.S., 2008. Antiproliferative and antimicrobial activity of traditional Kombucha and Satureja montana L. Kombucha. Journal of BUON, 13(3), 395-401.
Cetojevic-Simin, D.D., Canadanovic-Brunet, J.M., Bogdanovic, G.M., Cetkovic, G.S., Tumbas, V.T., Djilas, S.M., 2004. Antioxidative and antiproliferative effects of Satureja montana L. extracts. Journal of BUON, 9(4), 443-449.
Cetojevic-Simin, D.D., Velićanski, A.S., Cvetković, D.D., Markov, S.L., Mrđanović, J.Ž., Bogdanović, V.V., Šolajić, S.V., 2012. Bioactivity of lemon balm kombucha. Food and Bioprocess Technology, 5(5), 1756-1765.
Chorianopoulos, N., Evergetis, E., Mallouchos, A., Kalpoutzakis, E., Nychas, G.J., Haroutounian, S.A., 2006. Characterization of the essential oil volatiles of Satureja thymbra and Satureja parnassica: Influence of harvesting time and antimicrobial activity. Journal of Agricultural and Food Chemistry, 54(8), 3139-3145.
Davis, P.H., 1982. Flora of Turkey and The East Aegan Islands (Vol. 7). Edinburgh: Edinburgh University Press. Emre, İ., Kurşat, M., Yilmaz, Ö., Erecevit, P., 2020. Chemical compositions, radical scavenging capacities and antimicrobial activities in seeds of Satureja hortensis L. and Mentha spicata L. subsp. spicata from Turkey. Brazilian Journal of Biology, 81, 144-153.
Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., 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.
Friesner, R.A., Murphy, R.B., Repasky, M.P., Frye, L.L., Greenwood, J.R., Halgren, T.A., 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.
Giweli, A., Džamić, A.M., Soković, M., Ristić, M.S., Marin, P.D., 2012. Antimicrobial and antioxidant activities of essential oils of Satureja thymbra growing wild in Libya. Molecules, 17(5), 4836-4850.
Gohari, A.R., Saeidnia, S., Gohari, M.R., Moradi-Afrapoli, F., Malmir, M., Hadjiakhoondi, A., 2009. Bioactive flavonoids from Satureja atropatana Bonge. Natural Product Research, 23(17), 1609-1614.
Güllüce, M., Sökmen, M., Daferera, D., Aǧar, G., Özkan, H., Kartal, N., Şahin, F. (2003). In vitro antibacterial, antifungal, and antioxidant activities of the essential oil and methanol extracts of herbal parts and callus cultures of Satureja hortensis L. Journal of Agricultural and Food Chemistry, 51(14), 3958-3965.
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.
Hall Jr, D.C., Ji, H.F., 2020. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Medicine and Infectious Disease, 35, 101646.
Heinrich, M., 2000. Ethnobotany and its role in drug development. Phytotherapy Research, 14(7), 479-488.
Ilhan, E., Cesur, S., Guler, E., Topal, F., Albayrak, D., Guncu, M.M., Gunduz, O., 2020. Development of Satureja cuneifolia-loaded sodium alginate/polyethylene glycol scaffolds produced by 3D-printing technology as a diabetic wound dressing material. International Journal of Biological Macromolecules, 161, 1040-1054.
Jalali, A., Dabaghian, F., Akbrialiabad, H., Foroughinia, F., Zarshenas, M.M., 2021. A pharmacology‐based comprehensive review on medicinal plants and phytoactive constituents possibly effective in the management of COVID‐19. Phytotherapy Research, 35(4), 1925-1938.
Kosar, M., Dorman, H.J.D., Bachmayer, O., Baser, K.H.C., Hiltunen, R., 2003. An improved on-line HPLC-DPPH method for the screening of free radical scavenging compounds in water extracts of Lamiaceae plants. Chemistry of Natural Compounds, 39(2), 161-166.
Ligprep, M., Macromodel, G., 2011. QikProp; Schrodinger, LLC; New York.
Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J., 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23(1-3), 3-25.
Malmir, M., Gohari, A.R., Saeidnia, S., 2012. Flavonoids from the aerial parts of Satureja khuzestanica. Planta Medica, 78(11), PI365.
Moghaddam, F.M., Farimani, M.M., Salahvarzi, S., Amin, G., 2007. Chemical constituents of dichloromethane extract of cultivated Satureja khuzistanica. Evidence-Based Complementary and Alternative Medicine, 4(1), 95-98.
Momtaz, S., Abdollahi, M., 2010. An update on pharmacology of Satureja species; from antioxidant, antimicrobial, anti-diabetes and anti-hyperlipidemic to reproductive stimulation. International Journal of Pharmacology, 6(4), 454-461.
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.
Orhan, I.E., Deniz, F.S.S., 2020. Natural products as potential leads against coronaviruses: could they be encouraging structural models against SARS-CoV-2?. Natural Products and Bioprospecting, 10(4), 171-186.
Ozcelik, B., Kartal, M., Orhan, I., 2011. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharmaceutical Biology, 49(4), 396-402.
Palavra, A.M.F., Coelho, J.P., Barroso, J.G., Rauter, A.P., Fareleira, J.M.N.A., Mainar, A., ovais, J.M., 2011. Supercritical carbon dioxide extraction of bioactive compounds from microalgae and volatile oils from aromatic plants. The Journal of Supercritical Fluids, 60, 21-27.
Raja, R.R., 2012. Medicinally potential plants of Labiatae (Lamiaceae) family: an overview. Research Journal of Medicinal Plant, 6(3), 203-213.
Rajagopal, K., Varakumar, P., Aparna, B., Byran, G., Jupudi, S., 2021. Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies. Journal of Biomolecular Structure and Dynamics, 39(15), 5551-5562.
Rajagopal, K., Varakumar, P., Baliwada, A., Byran, G., 2020. Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach. Future Journal of Pharmaceutical Sciences, 6(1), 1-10.
Rauf, A., Rashid, U., Khalil, A.A., Khan, S.A., Anwar, S., Alafnan, A., Rengasamy, K.R., 2021. Docking-based virtual screening and identification of potential COVID-19 main protease inhibitors from brown algae. South African Journal of Botany, 143, 428-434.
Robson, F., Khan, K.S., Le, T.K., Paris, C., Demirbag, S., Barfuss, P., Ng, W.L., 2020. Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting. Molecular Cell, 79(5), 710-727.
Sahin, F., Karaman, I., Güllüce, M., Öğütçü, H., Şengül, M., Adıgüzel, A., Kotan, R., 2003. Evaluation of antimicrobial activities of Satureja hortensis L. Journal of Ethnopharmacology, 87(1), 61-65.
Silva, F.V., Martins, A., Salta, J., Neng, N.R., Nogueira, J.M., Mira, D., Rauter, A.P., 2009. Phytochemical profile and anticholinesterase and antimicrobial activities of supercritical versus conventional extracts of Satureja montana. Journal of Agricultural and Food Chemistry, 57(24), 11557-11563.
Skoula, M., Grayer, R.J., Kite, G.C., 2005. Surface flavonoids in Satureja thymbra and Satureja spinosa (Lamiaceae). Biochemical Systematics and Ecology, 33(5), 541-544.
Tepe, B., Cilkiz, M., 2016. A pharmacological and phytochemical overview on Satureja. Pharmaceutical Biology, 54(3), 375-412.
Thirumalaisamy, R., Aroulmoji, V., Iqbal, M.N., Deepa, M., Sivasankar, C., Khan, R., Selvankumar, T., 2021. Molecular insights of hyaluronic acid-hydroxychloroquine conjugate as a promising drug in targeting SARS-CoV-2 viral proteins. Journal of Molecular Structure, 1238, 130457.
Vosough-Ghanbari, S., Rahimi, R., Kharabaf, S., Zeinali, S., Mohammadirad, A., Amini, S., Abdollahi, M., 2010. Effects of Satureja khuzestanica on serum glucose, lipids and markers of oxidative stress in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial. Evidence-Based Complementary and Alternative Medicine, 7(4), 465-470.
Wax, R.S., Christian, M.D., 2020. Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019-nCoV) patients. Canadian Journal of Anesthesia/Journal canadien d'anesthésie, 67(5), 568-576.
Weiss, S.R., Navas-Martin, S., 2005. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiology and Molecular Biology Reviews, 69(4), 635-664.
WHO (World Health Organization), 2020. Coronavirus Disease (COVID-19) Dashboard. Retrieved from https://covid19.who.int/info.
Zargari, A., 1990. Medicinal Plants (Vol. 1). Tehran: Tehran University Press.