Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Lead Finding from Selected Flavonoids with Antiviral (SARS-CoV-2) Potentials Against COVID-19: An In-silico Evaluation

Author(s): Uma Sankar Gorla*, Koteswara Rao, Uma Sankar Kulandaivelu, Rajasekhar Reddy Alavala and Siva Prasad Panda

Volume 24, Issue 6, 2021

Published on: 18 August, 2020

Page: [879 - 890] Pages: 12

DOI: 10.2174/1386207323999200818162706

Price: $65

Abstract

Background: COVID-19 is a pandemic respiratory contagious viral (SARS-CoV-2) disease associated with high morbidity and mortality worldwide. Currently, there are no effective preventive or treatment strategies for COVID-19 and it has been declared as a global health emergency by WHO. In silico molecular docking studies can be useful to predict the binding affinity between the phytocompound and the target protein and play a vital role in finding an inhibitor through structure-based drug design.

Objective: In this aspect, our objective was to screen essential flavonoids against possible protein targets such as SARS-CoV-2 spike glycoprotein receptor binding domain (RBD-S) and host Angiotensin Converting Enzyme-2 protease domain (PD-ACE-2) using in silico molecular docking studies.

Methods: Approximately 49 flavonoids were identified and were evaluated for their drug-likeness based on Lipinski rule, bioactivity scores, antiviral and toxicity profiles using SwissADME, Molinspiration, PASS and GUSAR online tools. The flavonoids that passed Lipinski rule were subjected to in silico analysis through molecular docking on RBD-S and PD-ACE-2 using Molegro Virtual Docker v6.0.

Results: The bioactive flavonoids that showed NIL violations and were found in compliance with Lipinski rule were selected for docking studies. In silico analysis reported that biochanin A and silymarin bind significantly at the active sites of RBD-S and PD-ACE-2 with a MolDock score of -78.41and -121.28 kcal/mol respectively. Bioactivity scores, antiviral potential and toxicity profiles were predicted for the top interacting phytocompounds and substantial relevant data was reported.

Conclusion: The current outcomes created a new paradigm for understanding biochanin A and silymarin bioflavonoids as potent inhibitors of RBD-S and PD-ACE-2 targets respectively. Further work can be extended to confirm their therapeutic potential for COVID-19.

Keywords: COVID-19, SARS-CoV-2, Spike protein, ACE2, coronavirus, in silico molecular docking.

« Previous
[1]
Wu, F.; Zhao, S.; Yu, B.; Chen, Y.M.; Wang, W.; Song, Z.G.; Hu, Y.; Tao, Z.W.; Tian, J.H.; Pei, Y.Y.; Yuan, M.L.; Zhang, Y.L.; Dai, F.H.; Liu, Y.; Wang, Q.M.; Zheng, J.J.; Xu, L.; Holmes, E.C.; Zhang, Y.Z. A new coronavirus associated with human respiratory disease in China. Nature, 2020, 579(7798), 265-269.
[http://dx.doi.org/10.1038/s41586-020-2008-3] [PMID: 32015508]
[2]
Dhama, K.; Sharun, K.; Tiwari, R.; Dadar, M.; Malik, Y.S.; Singh, K.P.; Chaicumpa, W. COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics. Hum. Vaccin. Immunother., 2020, 16(6), 1232-1238.
[http://dx.doi.org/10.1080/21645515.2020.1735227] [PMID: 32186952]
[3]
Li, L.Q.; Huang, T.; Wang, Y.Q.; Wang, Z.P.; Liang, Y.; Huang, T.B.; Zhang, H.Y.; Sun, W.M.; Wang, Y.P. novel coronavirus patients’ clinical characteristics, discharge rate and fatality rate of meta‐analysis. J. Med. Virol., 2019, 2020(March), 1-7.
[4]
Baldwin, R.; di Mauro, B.W. Economics in the Time of COVID-19; a VoxEU.org eBook; CEPR Press, 2020.
[5]
Wang, Q.; Zhang, Y.; Wu, L.; Niu, S.; Song, C.; Zhang, Z.; Lu, G.; Qiao, C.; Hu, Y.; Yuen, K.Y.; Wang, Q.; Zhou, H.; Yan, J.; Qi, J. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell, 2020, 181(4), 894-904.e9.
[http://dx.doi.org/10.1016/j.cell.2020.03.045] [PMID: 32275855]
[6]
Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B, 2020, (February), 1-44.
[http://dx.doi.org/10.1016/j.apsb.2020.02.008] [PMID: 32292689]
[7]
Prajapat, M.; Sarma, P.; Shekhar, N.; Avti, P.; Sinha, S.; Kaur, H.; Kumar, S.; Bhattacharyya, A.; Kumar, H.; Bansal, S.; Medhi, B. Drug targets for corona virus: A systematic review. Indian J. Pharmacol., 2020, 52(1), 56-65.
[http://dx.doi.org/10.4103/ijp.IJP_115_20] [PMID: 32201449]
[8]
Zhang, H.; Penninger, J.M.; Li, Y.; Zhong, N.; Slutsky, A.S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med., 2020, 46(4), 586-590.
[http://dx.doi.org/10.1007/s00134-020-05985-9] [PMID: 32125455]
[9]
Zandi, K.; Teoh, B.T.; Sam, S.S.; Wong, P.F.; Mustafa, M.R.; Abubakar, S. Antiviral activity of four types of bioflavonoid against dengue virus type-2. Virol. J., 2011, 8(1), 560.
[http://dx.doi.org/10.1186/1743-422X-8-560] [PMID: 22201648]
[10]
Hakobyan, A.; Arabyan, E.; Avetisyan, A.; Abroyan, L.; Hakobyan, L.; Zakaryan, H. Apigenin inhibits African swine fever virus infection in vitro. Arch. Virol., 2016, 161(12), 3445-3453.
[http://dx.doi.org/10.1007/s00705-016-3061-y] [PMID: 27638776]
[11]
Chiang, L.C.; Ng, L.T.; Cheng, P.W.; Chiang, W.; Lin, C.C. Antiviral activities of extracts and selected pure constituents of Ocimum basilicum. Clin. Exp. Pharmacol. Physiol., 2005, 32(10), 811-816.
[http://dx.doi.org/10.1111/j.1440-1681.2005.04270.x] [PMID: 16173941]
[12]
Robin, V.; Irurzun, A.; Amoros, M.; Boustie, J.; Carrasco, L. Antipoliovirus flavonoids from Psiadia dentata. Antivir. Chem. Chemother., 2001, 12(5), 283-291.
[http://dx.doi.org/10.1177/095632020101200503] [PMID: 11900347]
[13]
Shimizu, J.F.; Lima, C.S.; Pereira, C.M.; Bittar, C.; Batista, M.N.; Nazaré, A.C.; Polaquini, C.R.; Zothner, C.; Harris, M.; Rahal, P.; Regasini, L.O.; Jardim, A.C.G. Flavonoids from pterogyne nitens inhibit hepatitis C virus entry. Sci. Rep., 2017, 7(1), 16127.
[http://dx.doi.org/10.1038/s41598-017-16336-y] [PMID: 29170411]
[14]
Dai, W.; Bi, J.; Li, F.; Wang, S.; Huang, X.; Meng, X.; Sun, B.; Wang, D.; Kong, W.; Jiang, C.; Su, W. Antiviral efficacy of flavonoids against enterovirus 71 infection in vitro and in newborn mice. Viruses, 2019, 11(7), 625.
[http://dx.doi.org/10.3390/v11070625] [PMID: 31284698]
[15]
Lyu, S.Y.; Rhim, J.Y.; Park, W.B. Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. Arch. Pharm. Res., 2005, 28(11), 1293-1301.
[http://dx.doi.org/10.1007/BF02978215] [PMID: 16350858]
[16]
Zakaryan, H.; Arabyan, E.; Oo, A.; Zandi, K. Flavonoids: promising natural compounds against viral infections. Arch. Virol., 2017, 162(9), 2539-2551.
[http://dx.doi.org/10.1007/s00705-017-3417-y] [PMID: 28547385]
[17]
Lu, H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci. Trends, 2020, 14(1), 69-71.
[http://dx.doi.org/10.5582/bst.2020.01020] [PMID: 31996494]
[18]
Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; Müller, M.A.; Drosten, C.; Pöhlmann, S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020, 181(2), 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[19]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[20]
Xia, S.; Liu, M.; Wang, C.; Xu, W.; Lan, Q.; Feng, S.; Qi, F.; Bao, L.; Du, L.; Liu, S.; Qin, C.; Sun, F.; Shi, Z.; Zhu, Y.; Jiang, S.; Lu, L. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res., 2020, 30(4), 343-355.
[http://dx.doi.org/10.1038/s41422-020-0305-x] [PMID: 32231345]
[21]
Shang, J.; Ye, G.; Shi, K.; Wan, Y.; Luo, C.; Aihara, H.; Geng, Q.; Auerbach, A.; Li, F. Structural basis of receptor recognition by SARS-CoV-2. Nature, 2020, 581(7807), 221-224.
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[22]
Miksicek, R.J. Estrogenic flavonoids: structural requirements for biological activity. Proc. Soc. Exp. Biol. Med., 1995, 208(1), 44-50.
[http://dx.doi.org/10.3181/00379727-208-43830] [PMID: 7892294]
[23]
Dornstauder, E.; Jisa, E.; Unterrieder, I.; Krenn, L.; Kubelka, W.; Jungbauer, A. Estrogenic activity of two standardized red clover extracts (Menoflavon) intended for large scale use in hormone replacement therapy. J. Steroid Biochem. Mol. Biol., 2001, 78(1), 67-75.
[http://dx.doi.org/10.1016/S0960-0760(01)00075-9] [PMID: 11530286]
[24]
Kole, L.; Giri, B.; Manna, S.K.; Pal, B.; Ghosh, S. Biochanin-A, an isoflavon, showed anti-proliferative and anti-inflammatory activities through the inhibition of iNOS expression, p38-MAPK and ATF-2 phosphorylation and blocking NFκB nuclear translocation. Eur. J. Pharmacol., 2011, 653(1-3), 8-15.
[http://dx.doi.org/10.1016/j.ejphar.2010.11.026] [PMID: 21147093]
[25]
Hanski, L.; Genina, N.; Uvell, H.; Malinovskaja, K.; Gylfe, Å.; Laaksonen, T.; Kolakovic, R.; Mäkilä, E.; Salonen, J.; Hirvonen, J.; Elofsson, M.; Sandler, N.; Vuorela, P.M. Inhibitory activity of the isoflavone biochanin A on intracellular bacteria of genus Chlamydia and initial development of a buccal formulation. PLoS One, 2014, 9(12)e115115
[http://dx.doi.org/10.1371/journal.pone.0115115] [PMID: 25514140]
[26]
Chen, Y.; Huang, C.; Zhou, T.; Zhang, S.; Chen, G. Biochanin A induction of sulfotransferases in rats. J. Biochem. Mol. Toxicol., 2010, 24(2), 102-114.
[http://dx.doi.org/10.1002/jbt.20318] [PMID: 20391625]
[27]
Azizi, R.; Goodarzi, M.T.; Salemi, Z. Effect of biochanin a on serum visfatin level of streptozocin-induced diabetic rats. Iran. Red Crescent Med. J., 2014, 16(9)e15424
[http://dx.doi.org/10.5812/ircmj.15424] [PMID: 25593725]
[28]
Sartorelli, P.; Carvalho, C.S.; Reimão, J.Q.; Ferreira, M.J.; Tempone, A.G. Antiparasitic activity of biochanin A, an isolated isoflavone from fruits of Cassia fistula (Leguminosae). Parasitol. Res., 2009, 104(2), 311-314.
[http://dx.doi.org/10.1007/s00436-008-1193-z] [PMID: 18810492]
[29]
Sithisarn, P.; Michaelis, M.; Schubert-Zsilavecz, M.; Cinatl, J., Jr Differential antiviral and anti-inflammatory mechanisms of the flavonoids biochanin A and baicalein in H5N1 influenza A virus-infected cells. Antiviral Res., 2013, 97(1), 41-48.
[http://dx.doi.org/10.1016/j.antiviral.2012.10.004] [PMID: 23098745]
[30]
Cirone, M.; Zompetta, C.; Tarasi, D.; Frati, L.; Faggioni, A. Infection of human T lymphoid cells by human herpesvirus 6 is blocked by two unrelated protein tyrosine kinase inhibitors, biochanin A and herbimycin. AIDS Res. Hum. Retroviruses, 1996, 12(17), 1629-1634.
[http://dx.doi.org/10.1089/aid.1996.12.1629] [PMID: 8947298]
[31]
Dixit, N.; Baboota, S.; Kohli, K.; Ahmad, S.; Ali, J. Silymarin: A review of pharmacological aspects and bioavailability enhancement approaches. Indian J. Pharmacol., 2007, 39(4), 172-179.
[http://dx.doi.org/10.4103/0253-7613.36534]
[32]
Lettéron, P.; Labbe, G.; Degott, C.; Berson, A.; Fromenty, B.; Delaforge, M.; Larrey, D.; Pessayre, D. Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem. Pharmacol., 1990, 39(12), 2027-2034.
[http://dx.doi.org/10.1016/0006-2952(90)90625-U] [PMID: 2353942]
[33]
De La Puerta, R.; Martinez, E.; Bravo, L.; Ahumada, M.C. Effect of silymarin on different acute inflammation models and on leukocyte migration. J. Pharm. Pharmacol., 1996, 48(9), 968-970.
[http://dx.doi.org/10.1111/j.2042-7158.1996.tb06014.x] [PMID: 8910865]
[34]
Won, D.H.; Kim, L.H.; Jang, B.; Yang, I.H.; Kwon, H.J.; Jin, B.; Oh, S.H.; Kang, J.H.; Hong, S.D.; Shin, J.A.; Cho, S.D. In vitro and in vivo anti-cancer activity of silymarin on oral cancer. Tumour Biol., 2018, 40(5)1010428318776170
[http://dx.doi.org/10.1177/1010428318776170] [PMID: 29764340]
[35]
Vostálová, J.; Tinková, E.; Biedermann, D.; Kosina, P.; Ulrichová, J.; Rajnochová Svobodová, A. Skin protective activity of silymarin and its flavonolignans. Molecules, 2019, 24(6), 1022.
[http://dx.doi.org/10.3390/molecules24061022] [PMID: 30875758]
[36]
Gharbia, S.; Balta, C.; Herman, H.; Rosu, M.; Váradi, J.; Bácskay, I.; Vecsernyés, M.; Gyöngyösi, S.; Fenyvesi, F.; Voicu, S.N.; Stan, M.S.; Cristian, R.E.; Dinischiotu, A.; Hermenean, A. Enhancement of silymarin anti-fibrotic effects by complexation with hydroxypropyl (HPBCD) and randomly methylated (RAMEB) β-cyclodextrins in a mouse model of liver fibrosis. Front. Pharmacol., 2018, 9, 883.
[http://dx.doi.org/10.3389/fphar.2018.00883] [PMID: 30150935]
[37]
Voroneanu, L.; Nistor, I.; Dumea, R.; Apetrii, M.; Covic, A. Silymarin in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J. Diabetes Res., 2016, 2016, 5147468.
[http://dx.doi.org/10.1155/2016/5147468] [PMID: 27340676]
[38]
Magliulo, E.; Gagliardi, B.; Fiori, G.P. [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres (author’s transl)]. Med. Klin., 1978, 73(28-29), 1060-1065.
[PMID: 353464]
[39]
Liu, C.H.; Jassey, A.; Hsu, H.Y.; Lin, L.T. Antiviral Activities of Silymarin and Derivatives. Molecules, 2019, 24(8), 1552.
[http://dx.doi.org/10.3390/molecules24081552] [PMID: 31010179]
[40]
Nijveldt, R.J.; van Nood, E.; van Hoorn, D.E.; Boelens, P.G.; van Norren, K.; van Leeuwen, P.A. Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr., 2001, 74(4), 418-425.
[http://dx.doi.org/10.1093/ajcn/74.4.418] [PMID: 11566638]
[41]
Panche, A.N.; Diwan, A.D.; Chandra, S.R. Flavonoids: an overview. J. Nutr. Sci., 2016, 5(47), e47.
[http://dx.doi.org/10.1017/jns.2016.41] [PMID: 28620474]
[42]
Rathee, P.; Chaudhary, H.; Rathee, S.; Rathee, D.; Kumar, V.; Kohli, K. Mechanism of action of flavonoids as anti-inflammatory agents: a review. Inflamm. Allergy Drug Targets, 2009, 8(3), 229-235.
[http://dx.doi.org/10.2174/187152809788681029] [PMID: 19601883]
[43]
Pietta, P.G. Flavonoids as antioxidants. J. Nat. Prod., 2000, 63(7), 1035-1042.
[http://dx.doi.org/10.1021/np9904509] [PMID: 10924197]
[44]
Mostafa, M.; Appidi, J.R.; Yakubu, M.T.; Afolayan, A.J. Anti-inflammatory, antinociceptive and antipyretic properties of the aqueous extract of Clematis brachiata leaf in male rats. Pharm. Biol., 2010, 48(6), 682-689.
[http://dx.doi.org/10.3109/13880200903257966] [PMID: 20645742]
[45]
Rodríguez-García, C.; Sánchez-Quesada, C.; J Gaforio, J. Dietary flavonoids as cancer chemopreventive agents: An updated review of human studies. Antioxidants, 2019, 8(5), 137.
[http://dx.doi.org/10.3390/antiox8050137] [PMID: 31109072]
[46]
Cushnie, T.P.; Lamb, A.J. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents, 2005, 26(5), 343-356.
[http://dx.doi.org/10.1016/j.ijantimicag.2005.09.002] [PMID: 16323269]
[47]
Kaul, T.N.; Middleton, E., Jr; Ogra, P.L. Antiviral effect of flavonoids on human viruses. J. Med. Virol., 1985, 15(1), 71-79.
[http://dx.doi.org/10.1002/jmv.1890150110] [PMID: 2981979]
[48]
Ahmad, A.; Kaleem, M.; Ahmed, Z.; Shafiq, H. Therapeutic potential of flavonoids and their mechanism of action against microbial and viral infections-A review. Food Res. Int., 2015, 77, 221-235.
[http://dx.doi.org/10.1016/j.foodres.2015.06.021]
[49]
Walls, A.C.; Park, Y.J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 2020, 181(2), 281-292.e6.
[http://dx.doi.org/10.1016/j.cell.2020.02.058] [PMID: 32155444]
[50]
Beigel, J.H.; Tomashek, K.M.; Dodd, L.E.; Mehta, A.K.; Zingman, B.S.; Kalil, A.C.; Hohmann, E.; Chu, H.Y.; Luetkemeyer, A.; Kline, S.; Lopez de Castilla, D. Remdesivir for the treatment of Covid-19-priliminary report. N. Engl. J. Med., 2020, (May), 1-12.
[51]
Colson, p.; Rolan, J.M.; Lagier, J.C.; Brouqui, P.; Raoult, D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Int. J. Antimicrob. Agents, 2020.
[52]
Velavan, T.P.; Meyer, C.G. The COVID-19 epidemic. Trop. Med. Int. Health, 2020, 25(3), 278-280.
[http://dx.doi.org/10.1111/tmi.13383] [PMID: 32052514]
[53]
Hung, I.F.; Lung, K.C.; Tso, E.Y.; Liu, R.; Chung, T.W.; Chu, M.Y.; Ng, Y.Y.; Lo, J.; Chan, J.; Tam, A.R.; Shum, H.P.; Chan, V.; Wu, A.K.; Sin, K.M.; Leung, W.S.; Law, W.L.; Lung, D.C.; Sin, S.; Yeung, P.; Yip, C.C.; Zhang, R.R.; Fung, A.Y.; Yan, E.Y.; Leung, K.H.; Ip, J.D.; Chu, A.W.; Chan, W.M.; Ng, A.C.; Lee, R.; Fung, K.; Yeung, A.; Wu, T.C.; Chan, J.W.; Yan, W.W.; Chan, W.M.; Chan, J.F.; Lie, A.K.; Tsang, O.T.; Cheng, V.C.; Que, T.L.; Lau, C.S.; Chan, K.H.; To, K.K.; Yuen, K.Y. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet, 2020, 395(10238), 1695-1704.
[http://dx.doi.org/10.1016/S0140-6736(20)31042-4] [PMID: 32401715]

Rights & Permissions Print Cite
Article Metrics
45
1
© 2024 Bentham Science Publishers | Privacy Policy