Exploring the Potency of Nigella sativa Seed in Inhibiting SARS-CoV-2 Main Protease Using Molecular Docking and Molecular Dynamics Simulations
Ari Hardianto(1*), Muhammad Yusuf(2), Ika Wiani Hidayat(3), Safri Ishmayana(4), Ukun Mochammad Syukur Soedjanaatmadja(5)
(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(*) Corresponding Author
Abstract
Coronavirus disease (COVID-19) is a pandemic burdening the global economy. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Black cumin (Nigella sativa) seed may contain antivirals for the disease since it was reported to inhibit the human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Main protease (Mpro) is a vital protein for viral replication and a promising target for COVID-19 drug development. Hence, in this study, we intended to uncover the potency of N. sativa seed as the natural source of inhibitors for SARS-CoV-2 Mpro. We collected secondary metabolites in N. sativa seed through a literature search and employed Lipinski’s rule of five as the initial filter. Subsequently, virtual screening campaigns using a molecular docking method were performed, with N3 inhibitor and leupeptin as reference ligands. The top hits were analyzed further using a molecular dynamics simulation approach. Molecular dynamics simulations showed that binding affinities of nigellamine A2 and A3 to Mpro are comparable to that of leupeptin, with median values of -43.9 and -36.2 kcal mol–1, respectively. Ultimately, this study provides scientific information regarding N. sativa seeds’ potency against COVID-19 and helps direct further wet experiments.
Keywords
References
[1] WHO, 2020, Pneumonia of unknown cause – China, https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/, accessed on May 16, 2021.
[2] Gorbalenya, A.E., Baker, S.C., Baric, R.S., de Groot, R.J., Drosten, C., Gulyaeva, A.A., Haagmans, B.L., Lauber, C., Leontovich, A.M., Neuman, B.W., Penzar, D., Perlman, S., Poon, L.L.M., Samborskiy, D.V., Sidorov, I.A., Sola, I., and Ziebuhr, J., 2020, The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2, Nat. Microbiol., 5 (4), 536–544.
[3] WHO, 2020, WHO announces COVID-19 outbreak a pandemic, http://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic, accessed on May 16, 2021.
[4] Mathieu, E., Ritchie, H., Ortiz-Ospina, E., Roser, M., Hasell, J., Appel, C., Giattino, C., and Rodés-Guirao, L., 2021, A global database of COVID-19 vaccinations, Nat. Hum. Behav., 5 (7), 947–953.
[5] Worldometers, 2021, COVID-19 coronavirus pandemic, https://www.worldometers.info/coronavirus/, accessed on May 16, 2021.
[6] Kneller, D.W., Galanie, S., Phillips, G., O’Neill, H.M., Coates, L., and Kovalevsky, A., 2020, Malleability of the SARS-CoV-2 3CL Mpro active-site cavity facilitates binding of clinical antivirals, Structure, 28 (12), 1313–1320.e3.
[7] Yimer, E.M., Tuem, K.B., Karim, A., Ur-Rehman, N., and Anwar, F., 2019, Nigella sativa L. (black cumin): A promising natural remedy for wide range of illnesses, Evidence-Based Complementary Altern. Med., 2019, 1528635.
[8] Khan, M.A., and Afzal, M., 2016, Chemical composition of Nigella sativa Linn: Part 2 Recent advances, Inflammopharmacology, 24 (2-3), 67–79.
[9] Ashraf, S., Ashraf, S., Ashraf, M., Imran, M.A., Kalsoom, L., Siddiqui, U.N., Farooq, I., Habib, Z., Ashraf, S., Ghufran, M., Akram, M.K., Majeed, N., Zain-ul-Abdin, Akmal, R., Rafique, S., Nawaz, K., Yousaf, M.I.K., Ahmad, S., Shahab, M.S., Nadeem, M.F., Azam, M., Zheng, H., Malik, A., Ayyaz, M., Mahmud, T., Saboor, Q.A., Ahmad, A., Ashraf, M., Izhar, M., Hilal, A., Muhammad, A., Shaukat, Z., Khaqan, A., Hayat, K., Arshad, S., Hassan, M., Abeer-bin-Awais, Ahmad, A., Mughal, T., Virk, A.R., Umer, M., Suhail, M., Zulfiqar, S., Sarfraz, S., Anwar, M.I., Humayun, A., Khokhar, R.A., and Siddique, S., 2020, Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): A multi-center placebo-controlled randomized clinical trial, medRxiv, Preprint article, has not been reviewed.
[10] Nickavar, B., Mojab, F., Javidnia, K., and Amoli, M.A.R., 2003, Chemical composition of the fixed and volatile oils of Nigella sativa L. from Iran, Z. Naturforsch., C: Biosci., 58 (9-10), 629–631.
[11] Ahmad, A., Husain, A., Mujeeb, M., Khan, S.A., Najmi, A.K., Siddique, N.A., Damanhouri, Z.A., and Anwar, F., 2013, A review on therapeutic potential of Nigella sativa: A miracle herb, Asian Pac. J. Trop. Biomed., 3 (5), 337–352.
[12] Mehta, B.K., Pandit, V., and Gupta, M., 2009, New principles from seeds of Nigella sativa, Nat. Prod. Res., 23 (2), 138–148.
[13] Merfort, I., Wray, V., Barakat, H.H., Hussein, S.A.M., Nawwar, M.A.M., and Willuhn, G., 1997, Flavonol triglycosides from seeds of Nigella sativa, Phytochemistry, 46 (2), 359–363.
[14] Yuan, T., Nahar, P., Sharma, M., Liu, K., Slitt, A., Aisa, H.A., and Seeram, N.P., 2014, Indazole-type alkaloids from Nigella sativa seeds exhibit antihyperglycemic effects via AMPK activation in vitro, J. Nat. Prod., 77 (10), 2316–2320.
[15] Morikawa, T., Xu, F., Ninomiya, K., Matsuda, H., and Yoshikawa, M., 2004, Nigellamines A3, A4, A5, and C, new dolabellane-type diterpene alkaloids, with lipid metabolism-promoting activities from the Egyptian medicinal food black cumin, Chem. Pharm. Bull., 52 (4), 494–497.
[16] Yusuf, M., Hardianto, A., Muchtaridi, M., Nuwarda, R.F., and Subroto, T., 2019, “Introduction of Docking-Based Virtual Screening Workflow Using Desktop Personal Computer” in Encyclopedia of Bioinformatics and Computational Biology, Volume 2, Eds. Ranganathan, S., Gribskov, M., Nakai, K., and Schönbach, B., Academic Press, Oxford, 688–699.
[17] Khan, S.L., Siddiqui, F.A., Jain, S.P., and Sonwane, G.M., 2021, Discovery of potential inhibitors of SARS-CoV-2 (COVID-19) Main Protease (Mpro) from Nigella Sativa (black seed) by molecular docking study, Coronaviruses, 2 (3), 384–402.
[18] Bouchentouf, S., and Missoum, N., 2020, Identification of compounds from Nigella Sativa as new potential inhibitors of 2019 novel Coronasvirus (Covid-19): Molecular docking study, Preprints, 2020, 2020040079.
[19] Maiti, S., Banerjee, A., Nazmeen, A., Kanwar, M., and Das, S., 2020, Active-site molecular docking of Nigellidine with nucleocapsid-NSP2-MPro of COVID-19 and to human IL1R-IL6R and strong antioxidant role of Nigella-sativa in experimental rats, J. Drug Targeting, 0 (ja), 1–23.
[20] Sumaryada, T., and Pramudita, C.A., 2021, Molecular docking evaluation of some Indonesian’s popular herbals for a possible COVID-19 treatment, Biointerface Res. Appl. Chem., 11 (3), 9827–9835.
[21] Ferdian, P.R., Elfirta, R.R., Emilia, Q., and Ikhwani, A.Z.N., 2020, Inhibitory potential of black seed (Nigella sativa L.) bioactive compounds towards main protease of SARS-CoV-2: In silico study, Ann. Bogor., 24 (2), 81–94.
[22] Forli, S., Huey, R., Pique, M.E., Sanner, M.F., Goodsell, D.S., and Olson, A.J., 2016, Computational protein–ligand docking and virtual drug screening with the AutoDock suite, Nat. Protoc., 11 (5), 905–919.
[23] Hardianto, A., Khanna, V., Liu, F., and Ranganathan, S., 2019, Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCϵ, BMC Bioinf., 19 (13), 187–197.
[24] Hardianto, A., Yusuf, M., Liu, F., and Ranganathan, S., 2017, Exploration of charge states of balanol analogues acting as ATP-competitive inhibitors in kinases, BMC Bioinf., 18 (16), 19–29.
[25] Hardianto, A., Liu, F., and Ranganathan, S., 2018, Molecular dynamics pinpoint the global fluorine effect in balanoids binding to PKCε and PKA, J. Chem. Inf. Model., 58 (2), 511–519.
[26] Lipinski, C.A., 2016, Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions, Adv. Drug Delivery Rev., 101, 34–41.
[27] Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., Nakatsuji, H., Li, X., Caricato, M., Marenich, A., Bloino, J., Janesko, B.G., Gomperts, R., Mennucci, B., Hratchian, H.P., Ortiz, J.V., Izmaylov, A.F., Sonnenberg, J.L., Williams-Young, D., Ding, F., Lipparini, F., Egidi, F., Goings, J., Peng, B., Petrone, A., Henderson, T., Ranasinghe, D., Zakrzewski, V.G., Gao, J., Rega, N., Zheng, G., Liang, W., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Throssell, K., Montgomery, Jr., J.A., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Keith, T., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Millam, J.M., Klene, M., Adamo, C., Cammi, R., Ochterski, J.W., Martin, R.L., Morokuma, K., Farkas, O., Foresman, J.B., and Fox, D.J., 2016, Gaussian 09 Revision A.02, Gaussian, Inc., Wallingford CT.
[28] Case, D.A., Aktulga, H.M., Belfon, K., Ben-Shalom, I.Y., Brozell, S.R., Cerutti, D.S., Cheatham, III, T.E., Cruzeiro, V.W.D., Darden, T.A., Duke, R.E., Giambasu, G., Gilson, M.K., Gohlke, H., Goetz, A.W., Harris, R., Izadi, S., Izmailov, S.A., Jin, C., Kasavajhala, K., Kaymak, M.C., King, E., Kovalenko, A., Kurtzman, T., Lee, T.S., LeGrand, S., Li, P., Lin, C., Liu, J., Luchko, T., Luo, R., Machado, M., Man, V., Manathunga, M., Merz, K.M., Miao, Y., Mikhailovskii, O., Monard, G., Nguyen, H., O’Hearn, K.A., Onufriev, A., Pan, F., Pantano, S., Qi, R., Rahnamoun, A., Roe, D.R., Roitberg, A., Sagui, C., Schott-Verdugo, S., Shen, J., Simmerling, C.L., Skrynnikov, N.R., Smith, J., Swails, J., Walker, R.C., Wang, J., Wei, H., Wolf, R.M., Wu, X., Xue, Y., York, D.M., Zhao, S., and Kollman, P.A., 2020, Amber 2020, University of California, San Francisco.
[29] Maier, J.A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K.E., and Simmerling, C., 2015, ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB, J. Chem. Theory Comput., 11 (8), 3696–3713.
[30] Egbert, M., Whitty, A., Keserű, G.M., and Vajda, S., 2019, Why some targets benefit from beyond rule of five drugs, J. Med. Chem., 62 (22), 10005–10025.
[31] Torres, P.H.M., Sodero, A.C.R., Jofily, P., and Silva-Jr, F.P., 2019, Key topics in molecular docking for drug design, Int. J. Mol. Sci., 20 (18), 4574.
[32] Singh, N., Villoutreix, B.O., and Ecker, G.F., 2019, Rigorous sampling of docking poses unveils binding hypothesis for the halogenated ligands of L-type Amino acid Transporter 1 (LAT1), Sci. Rep., 9 (1), 15061.
[33] Stewart, J.J.P., 2009, Application of the PM6 method to modeling proteins, J. Mol. Model., 15 (7), 765–805.
[34] Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L.W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., and Yang, H., 2020, Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors, Nature, 582 (7811), 289–293.
[35] Simmons, G., Gosalia, D.N., Rennekamp, A.J., Reeves, J.D., Diamond, S.L., and Bates, P., 2005, Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry, Proc. Natl. Acad. Sci. U.S.A., 102 (33), 11876–11881.
DOI: https://doi.org/10.22146/ijc.65951
Article Metrics
Abstract views : 4913 | views : 2894 | views : 1074Copyright (c) 2021 Indonesian Journal of Chemistry
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.
View The Statistics of Indones. J. Chem.