Abstract
Background: The COVID-19 pandemic emerged at the end of 2019 in China and spread rapidly all over the world. Scientists strive to find virus-specific antivirals against COVID-19 disease. This study aimed to assess some flavolignans as potential SARS-CoV-2 main protease (SARS-CoV-2 Mpro) inhibitors using molecular docking study, molecular dynamic simulations, and ADME analysis.
Methods: The detailed interactions between the flavolignans and SARS-CoV-2 Mpro were determined using Autodock 4.2 software. SARS-CoV-2 Mpro was docked with selected flavolignans, and the docking results were analyzed by Autodock 4.2 and Biovia Discovery Studio 4.5. The SARS-CoV-2 Mpro-flavolignans’ complexes were subjected to molecular dynamic (MD) simulations for a period of 50 ns. To measure the stability, flexibility, and average distance between the SARS-CoV-2 Mpro and flavolignans, root mean square deviations (RMSD) and root mean square fluctuation (RMSF) were calculated, and the binding free energy calculations of SARS-CoV-2 Mpro-flavolignans complexes were found to using the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) method. SwissADME web tools were used to evaluate ADME properties and pharmacokinetic parameters of the flavolignans.
Results: The binding energies of the SARS-CoV-2 Mpro- flavolignans’ complexes were identified from the molecular docking of SARS-CoV-2 Mpro. Sinaiticin was found to be the highest binding affinity of -9.4 kcal/mol and formed π-lone pair and pi-alkyl interactions with the catalytic binding residues Glu166 and Cys145. Silychristin, Dehydrosilybin, Hydrocarpin, Silydianin, and 5’- metoxyhydcaprin also showed high binding affinities of -9.3, -9.2, -9.0, -8.7 and -8.6 kcal/mol, respectively. The flavolignans demonstrated strong Carbon H bond interactions with the binding site residues of the Gln192, Gly143, Leu27, Glu166, and Tyr54, and thereby can act as potent inhibitors of the SARS-CoV 2 Mpro.
Conclusion: The selected flavolignans obey Lipinski’s rule of five. According to the results obtained from molecular docking studies, molecular dynamic simulations, and ADME analysis, it can be proposed that the flavolignans, which can be used to design effective antiviral drug candidates against the SARS-CoV-2, can be tried for promising and effective inhibitors of the SARS-CoV-2 main protease in vitro and in vivo studies.
Keywords: Antiviral activity, COVID-2019, flavolignan, docking, drugscore
Graphical Abstract
[1]
Zheng, J. SARS-CoV-2: An emerging coronavirus that causes a global threat. Int. J. Biol. Sci., 2020, 16(10), 1678-1685.
[http://dx.doi.org/10.7150/ijbs.45053] [PMID: 32226285]
[http://dx.doi.org/10.7150/ijbs.45053] [PMID: 32226285]
[2]
Fisher, D.; Heymann, D. Q&A: The novel coronavirus outbreak causing COVID-19. BMC Med., 2020, 18(1), 57.
[http://dx.doi.org/10.1186/s12916-020-01533-w] [PMID: 32106852]
[http://dx.doi.org/10.1186/s12916-020-01533-w] [PMID: 32106852]
[3]
Hebbani, A.V.; Pulakuntla, S.; Pannuru, P.; Aramgam, S.; Badri, K.R.; Reddy, V.D. COVID-19: Comprehensive review on mutations and current vaccines. Arch. Microbiol., 2021, 204(1), 8.
[http://dx.doi.org/10.1007/s00203-021-02606-x] [PMID: 34873656]
[http://dx.doi.org/10.1007/s00203-021-02606-x] [PMID: 34873656]
[4]
Ita, K. Coronavirus disease (COVID-19): Current status and prospects for drug and vaccine development. Arch. Med. Res., 2021, 52(1), 15-24.
[http://dx.doi.org/10.1016/j.arcmed.2020.09.010] [PMID: 32950264]
[http://dx.doi.org/10.1016/j.arcmed.2020.09.010] [PMID: 32950264]
[5]
Khairan, K.; Idroes, R.; Tallei, T.E.; Nasim, M.J.; Jacob, C. Bioactive compounds from medicinal plants and their possible effect as therapeutic agents against COVID-19: A review. Curr. Nutr. Food Sci., 2021, 17(6), 621-633.
[http://dx.doi.org/10.2174/1573401317999210112201439]
[http://dx.doi.org/10.2174/1573401317999210112201439]
[6]
Xia, L.; Shi, Y.; Su, J.; Friedemann, T.; Tao, Z.; Lu, Y.; Ling, Y.; Lv, Y.; Zhao, R.; Geng, Z.; Cui, X.; Lu, H.; Schröder, S. Shufeng Jiedu, a promising herbal therapy for moderate COVID-19:Antiviral and anti-inflammatory properties, pathways of bioactive compounds, and a clinical real-world pragmatic study. Phytomedicine, 2021, 85, 153390.
[http://dx.doi.org/10.1016/j.phymed.2020.153390] [PMID: 33158717]
[http://dx.doi.org/10.1016/j.phymed.2020.153390] [PMID: 33158717]
[7]
Khan, S.A.; Al-Balushi, K. Combating COVID-19: The role of drug repurposing and medicinal plants. J. Infect. Public Health, 2021, 14(4), 495-503.
[http://dx.doi.org/10.1016/j.jiph.2020.10.012] [PMID: 33743371]
[http://dx.doi.org/10.1016/j.jiph.2020.10.012] [PMID: 33743371]
[8]
Lim, X.Y.; Teh, B.P.; Tan, T.Y.C. Medicinal plants in COVID-19: Potential and limitations. Front. Pharmacol., 2021, 12, 611408.
[http://dx.doi.org/10.3389/fphar.2021.611408] [PMID: 33841143]
[http://dx.doi.org/10.3389/fphar.2021.611408] [PMID: 33841143]
[9]
Plant biotechnology: Experience and future prospects; Ricroch, A.; Chopra, S.; Kuntz, M., Eds.; Springer Nature, 2021.
[http://dx.doi.org/10.1007/978-3-030-68345-0]
[http://dx.doi.org/10.1007/978-3-030-68345-0]
[10]
Solnier, J.; Fladerer, J.P. Flavonoids: A complementary approach to conventional therapy of COVID-19? Phytochem. Rev., 2021, 20(4), 773-795.
[http://dx.doi.org/10.1007/s11101-020-09720-6] [PMID: 32982616]
[http://dx.doi.org/10.1007/s11101-020-09720-6] [PMID: 32982616]
[11]
Chen, L.; Cao, H.; Huang, Q.; Xiao, J.; Teng, H. Absorption, metabolism and bioavailability of flavonoids: A review. Crit. Rev. Food Sci. Nutr., 2021, 1-13.
[http://dx.doi.org/10.1080/10408398.2021.1917508] [PMID: 34078189]
[http://dx.doi.org/10.1080/10408398.2021.1917508] [PMID: 34078189]
[12]
Liskova, A.; Samec, M.; Koklesova, L.; Samuel, S.M.; Zhai, K.; Al-Ishaq, R.K.; Abotaleb, M.; Nosal, V.; Kajo, K.; Ashrafizadeh, M.; Zarrabi, A.; Brockmueller, A.; Shakibaei, M.; Sabaka, P.; Mozos, I.; Ullrich, D.; Prosecky, R.; La Rocca, G.; Caprnda, M.; Büsselberg, D.; Rodrigo, L.; Kruzliak, P.; Kubatka, P. Flavonoids against the SARS-CoV-2 induced inflammatory storm. Biomed. Pharmacother., 2021, 138, 111430.
[http://dx.doi.org/10.1016/j.biopha.2021.111430] [PMID: 33662680]
[http://dx.doi.org/10.1016/j.biopha.2021.111430] [PMID: 33662680]
[13]
Tsimogiannis, D.; Oreopoulou, V. Classification of phenolic compounds in plants. Polyphenols in plants; Academic Press, 2019, pp. 263-284.
[http://dx.doi.org/10.1016/B978-0-12-813768-0.00026-8]
[http://dx.doi.org/10.1016/B978-0-12-813768-0.00026-8]
[14]
Tungmunnithum, D.; Thongboonyou, A.; Pholboon, A.; Yangsabai, A. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines (Basel), 2018, 5(3), 93.
[http://dx.doi.org/10.3390/medicines5030093] [PMID: 30149600]
[http://dx.doi.org/10.3390/medicines5030093] [PMID: 30149600]
[15]
Giofrè, S.V.; Napoli, E.; Iraci, N.; Speciale, A.; Cimino, F.; Muscarà, C.; Molonia, M.S.; Ruberto, G.; Saija, A. Interaction of selected terpenoids with two SARS-CoV-2 key therapeutic targets: An in silico study through molecular docking and dynamics simulations. Comput. Biol. Med., 2021, 134, 104538.
[http://dx.doi.org/10.1016/j.compbiomed.2021.104538] [PMID: 34116362]
[http://dx.doi.org/10.1016/j.compbiomed.2021.104538] [PMID: 34116362]
[16]
Gyebi, G.A.; Ogunyemi, O.M.; Ibrahim, I.M.; Ogunro, O.B.; Adegunloye, A.P.; Afolabi, S.O. SARS-CoV-2 host cell entry: An in silico investigation of potential inhibitory roles of terpenoids. J. Genet. Eng. Biotechnol., 2021, 19(1), 113.
[http://dx.doi.org/10.1186/s43141-021-00209-z] [PMID: 34351542]
[http://dx.doi.org/10.1186/s43141-021-00209-z] [PMID: 34351542]
[17]
Boozari, M.; Hosseinzadeh, H. Natural products for COVID-19 prevention and treatment regarding to previous coronavirus infections and novel studies. Phytother. Res., 2021, 35(2), 864-876.
[http://dx.doi.org/10.1002/ptr.6873] [PMID: 32985017]
[http://dx.doi.org/10.1002/ptr.6873] [PMID: 32985017]
[18]
Ahmad, P.; Alvi, S.S.; Iqbal, J.; Khan, M.S. Identification and evaluation of natural organosulfur compounds as potential dual inhibitors of α-amylase and α-glucosidase activity: An in-silico and in-vitro approach. Med. Chem. Res., 2021, 30(12), 2184-2202.
[http://dx.doi.org/10.1007/s00044-021-02799-2]
[http://dx.doi.org/10.1007/s00044-021-02799-2]
[19]
Cetin, A. In silico studies on stilbenolignan analogues as SARS-CoV-2 Mpro inhibitors. Chem. Phys. Lett., 2021, 771, 138563.
[http://dx.doi.org/10.1016/j.cplett.2021.138563] [PMID: 33776065]
[http://dx.doi.org/10.1016/j.cplett.2021.138563] [PMID: 33776065]
[20]
Molavi, Z.; Razi, S.; Mirmotalebisohi, S.A.; Adibi, A.; Sameni, M.; Karami, F.; Niazi, V.; Niknam, Z.; Aliashrafi, M.; Taheri, M.; Ghafouri-Fard, S.; Jeibouei, S.; Mahdian, S.; Zali, H.; Ranjbar, M.M.; Yazdani, M. Identification of FDA approved drugs against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and 3-chymotrypsin-like protease (3CLpro), drug repurposing approach. Biomed. Pharmacother., 2021, 138, 111544.
[http://dx.doi.org/10.1016/j.biopha.2021.111544] [PMID: 34311539]
[http://dx.doi.org/10.1016/j.biopha.2021.111544] [PMID: 34311539]
[21]
Das, S.K.; Mahanta, S.; Tanti, B.; Tag, H.; Hui, P.K. Identification of phytocompounds from Houttuynia cordata thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC-MS/LC-MS characterization, molecular docking and molecular dynamics simulation. Mol. Divers., 2022, 26(1), 365-388.
[http://dx.doi.org/10.1007/s11030-021-10226-2] [PMID: 33961167]
[http://dx.doi.org/10.1007/s11030-021-10226-2] [PMID: 33961167]
[22]
Rachedi, K.O.; Ouk, T.S.; Bahadi, R.; Bouzina, A.; Djouad, S.E.; Bechlem, K.; Berredjem, M. Synthesis, DFT and POM analyses of cytotoxicity activity of α-amidophosphonates derivatives: Identification of potential antiviral O, O-pharmacophore site. J. Mol. Struct., 2019, 1197, 196-203.
[http://dx.doi.org/10.1016/j.molstruc.2019.07.053]
[http://dx.doi.org/10.1016/j.molstruc.2019.07.053]
[23]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[24]
Ji, B.; Liu, S.; He, X.; Man, V.H.; Xie, X.Q.; Wang, J. Prediction of the binding affinities and selectivity for CB1 and CB2 ligands using homology modeling, molecular docking, molecular dynamics simulations, and MM-PBSA binding free energy calculations. ACS Chem. Neurosci., 2020, 11(8), 1139-1158.
[http://dx.doi.org/10.1021/acschemneuro.9b00696] [PMID: 32196303]
[http://dx.doi.org/10.1021/acschemneuro.9b00696] [PMID: 32196303]
[25]
Hazra, T.; Ahmed Ullah, S.; Wang, S.; Alexov, E.; Zhao, S. A super-Gaussian Poisson-Boltzmann model for electrostatic free energy calculation: Smooth dielectric distribution for protein cavities and in both water and vacuum states. J. Math. Biol., 2019, 79(2), 631-672.
[http://dx.doi.org/10.1007/s00285-019-01372-1] [PMID: 31030299]
[http://dx.doi.org/10.1007/s00285-019-01372-1] [PMID: 31030299]
[26]
Kuriata, A.; Gierut, A.M.; Oleniecki, T.; Ciemny, M.P.; Kolinski, A.; Kurcinski, M.; Kmiecik, S. CABS-flex 2.0: A web server for fast simulations of flexibility of protein structures. Nucleic Acids Res., 2018, 46(W1), W338-W343.
[http://dx.doi.org/10.1093/nar/gky356] [PMID: 29762700]
[http://dx.doi.org/10.1093/nar/gky356] [PMID: 29762700]
[27]
Petukh, M.; Li, M.; Alexov, E. Predicting binding free energy change caused by point mutations with knowledge-modified MM/PBSA method. PLOS Comput. Biol., 2015, 11(7), e1004276.
[http://dx.doi.org/10.1371/journal.pcbi.1004276] [PMID: 26146996]
[http://dx.doi.org/10.1371/journal.pcbi.1004276] [PMID: 26146996]
[28]
Mothay, D.; Ramesh, K.V. Binding site analysis of potential protease inhibitors of COVID-19 using AutoDock. Virusdisease, 2020, 31(2), 194-199.
[http://dx.doi.org/10.1007/s13337-020-00585-z] [PMID: 32363219]
[http://dx.doi.org/10.1007/s13337-020-00585-z] [PMID: 32363219]
[29]
Kuca, K.; Musilek, K.; Jun, D.; Zdarova-Karasova, J.; Nepovimova, E.; Soukup, O.; Hrabinova, M.; Mikler, J.; Franca, T.C.C.; Da Cunha, E.F.F.; De Castro, A.A.; Valis, M.; Ramalho, T.C. A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase. BMC Pharmacol. Toxicol., 2018, 19(1), 8.
[http://dx.doi.org/10.1186/s40360-018-0196-3] [PMID: 29467029]
[http://dx.doi.org/10.1186/s40360-018-0196-3] [PMID: 29467029]
[30]
Rutwick, S.U.; Praveen, N. A molecular docking study of SARS-CoV-2 main protease against phytochemicals of Boerhavia diffusa Linn. for novel COVID-19 drug discovery. Virusdisease, 2021, 32(1), 46-54.
[http://dx.doi.org/10.1007/s13337-021-00683-6] [PMID: 33758772]
[http://dx.doi.org/10.1007/s13337-021-00683-6] [PMID: 33758772]
[31]
Gogoi, B.; Chowdhury, P.; Goswami, N.; Gogoi, N.; Naiya, T.; Chetia, P.; Mahanta, S.; Chetia, D.; Tanti, B.; Borah, P.; Handique, P.J. Identification of potential plant-based inhibitor against viral proteases of SARS-CoV-2 through molecular docking, MM-PBSA binding energy calculations and molecular dynamics simulation. Mol. Divers., 2021, 25(3), 1963-1977.
[http://dx.doi.org/10.1007/s11030-021-10211-9] [PMID: 33856591]
[http://dx.doi.org/10.1007/s11030-021-10211-9] [PMID: 33856591]
[32]
Saha, J.K.; Raihan, M.J. The binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2. Struct. Chem., 2021, 32(5), 1-8.
[http://dx.doi.org/10.1007/s11224-021-01776-0] [PMID: 33867777]
[http://dx.doi.org/10.1007/s11224-021-01776-0] [PMID: 33867777]
[33]
Beck, B.R.; Shin, B.; Choi, Y.; Park, S.; Kang, K. Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model. Comput. Struct. Biotechnol. J., 2020, 18, 784-790.
[http://dx.doi.org/10.1016/j.csbj.2020.03.025] [PMID: 32280433]
[http://dx.doi.org/10.1016/j.csbj.2020.03.025] [PMID: 32280433]
[34]
Ramalingam, A.K.; Selvi, S.G.A.; Jayaseelan, V.P. Targeting prolyl tripeptidyl peptidase from Porphyromonas gingivalis with the bioactive compounds from Rosmarinus officinalis. Asian Biomed., 2020, 13(5), 197-203.
[http://dx.doi.org/10.1515/abm-2019-0061]
[http://dx.doi.org/10.1515/abm-2019-0061]
[35]
da Silva, M.A.; Veloso, M.P.; de Souza Reis, K.; de Matos Passarini, G.; Dos Santos, A.P.A.; do Nascimento Martinez, L.; Fokoue, H.H.; Kato, M.J.; Teles, C.B.G.; Kuehn, C.C. In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs. Parasitol. Res., 2020, 119(6), 1879-1887.
[http://dx.doi.org/10.1007/s00436-020-06681-9] [PMID: 32382989]
[http://dx.doi.org/10.1007/s00436-020-06681-9] [PMID: 32382989]
[36]
Kurcinski, M.; Oleniecki, T.; Ciemny, M.P.; Kuriata, A.; Kolinski, A.; Kmiecik, S. CABS-flex standalone: A simulation environment for fast modeling of protein flexibility. Bioinformatics, 2019, 35(4), 694-695.
[http://dx.doi.org/10.1093/bioinformatics/bty685] [PMID: 30101282]
[http://dx.doi.org/10.1093/bioinformatics/bty685] [PMID: 30101282]
[37]
Damm, K.L.; Carlson, H.A. Gaussian-weighted RMSD superposition of proteins: A structural comparison for flexible proteins and predicted protein structures. Biophys. J., 2006, 90(12), 4558-4573.
[http://dx.doi.org/10.1529/biophysj.105.066654] [PMID: 16565070]
[http://dx.doi.org/10.1529/biophysj.105.066654] [PMID: 16565070]
[38]
Rocchia, W.; Alexov, E.; Honig, B. Extending the applicability of the nonlinear Poisson-Boltzmann equation: Multiple dielectric constants and multivalent ions. J. Phys. Chem. B, 2001, 105(28), 6507-6514.
[http://dx.doi.org/10.1021/jp010454y]
[http://dx.doi.org/10.1021/jp010454y]
[39]
Varughese, J.K.; Joseph Libin, K.L.; Sindhu, K.S.; Rosily, A.V.; Abi, T.G. Investigation of the inhibitory activity of some dietary bioactive flavonoids against SARS-CoV-2 using molecular dynamics simulations and MM-PBSA calculations. J. Biomol. Struct. Dyn., 2021, 1-16. [Online ahead of print]
[http://dx.doi.org/10.1080/07391102.2021.1891139] [PMID: 33618628]
[http://dx.doi.org/10.1080/07391102.2021.1891139] [PMID: 33618628]
[40]
Sang, P.; Tian, S.H.; Meng, Z.H.; Yang, L.Q. Anti-HIV drug repurposing against SARS-CoV-2. RSC Advances, 2020, 10(27), 15775-15783.
[http://dx.doi.org/10.1039/D0RA01899F] [PMID: 35493667]
[http://dx.doi.org/10.1039/D0RA01899F] [PMID: 35493667]
[41]
Baby, K.; Maity, S.; Mehta, C.H.; Suresh, A.; Nayak, U.Y.; Nayak, Y. Targeting SARS-CoV-2 main protease: A computational drug repurposing study. Arch. Med. Res., 2021, 52(1), 38-47.
[http://dx.doi.org/10.1016/j.arcmed.2020.09.013] [PMID: 32962867]
[http://dx.doi.org/10.1016/j.arcmed.2020.09.013] [PMID: 32962867]
Article Metrics
1