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Letters in Drug Design & Discovery

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Research Article

Screening Active Phytochemicals of Some Ayurvedic Medicinal Plants to Identify Potential Inhibitors against SARS-CoV-2 Mpro by Computational Investigation

Author(s): V. Alagarsamy*, V. Raja Solomon, M. T. Sulthana, P. Shyam Sundar, A. Dharshini Aishwarya and B. Narendhar

Volume 20, Issue 9, 2023

Published on: 25 October, 2022

Page: [1380 - 1392] Pages: 13

DOI: 10.2174/1570180819666220929151127

Price: $65

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) is an important target for drug development amidst whole variants of coronaviruses, a vital protein for the replication cycle of virus.

Objective: The main aim of this study is to discover and recognize the most effective and promising molecules against Mpro enzyme through molecular docking screening of 120 phytochemicals from six different Ayurveda medicinal plants.

Methods: The phytochemicals were downloaded from PubChem, and SARS-CoV-2 Mpro was taken from the protein data bank. The molecular interactions, binding energy, and ADMET properties were analyzed.

Results: Molecular docking analysis identified 10 phytochemicals, castalagin (-10.4 kcal/mol), wedelolactone (-8.0 kcal/mol), arjungenin (-7.7 kcal/mol), betulin (-7.7 kcal/mol), galbacin (-7.6 kcal/mol), shinpterocarpin (-7.6 kcal/mol), liquirtin (-7.4 kcal/mol), cordioside (-7.3 kcal/mol), licopyranocoumarin (-7.3 kcal/mol), and daucosterol (-7.1 kcal/mol) from different kinds of ayurvedic medicinal plants’ phytochemicals possessing greater affinity against Mpro of SARS-CoV-2. Two molecules, namely castalagin and wedelolactone, with low binding energies were the most promising. Furthermore, we carried out MD simulations for the castalagin complexes based on the docking score.

Conclusion: Molecular ADMET profile estimation showed the docked phytochemicals to be safe. The present study suggested that active phytochemicals from medicinal plants could inhibit Mpro of SARSCoV- 2.

Keywords: COVID-19, SARS-CoV-2 Mpro, molecular docking, MD simulation, Ayurveda, medicinal plants, ADMET.

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[1]
Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G.F.; Tan, W. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med., 2020, 382(8), 727-733.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[2]
Chen, Y.; Liu, Q.; Guo, D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J. Med. Virol., 2020, 92(4), 418-423.
[http://dx.doi.org/10.1002/jmv.25681] [PMID: 31967327]
[3]
Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.; Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020, 395(10223), 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[4]
Israeli, E. Novel coronavirus that recently emerged in China. Harefuah, 2020, 159(1), 70-71.
[PMID: 32048481]
[5]
Sumon, T.A.; Hussain, M.A.; Hasan, M.T.; Hasan, M.; Jang, W.J.; Bhuiya, E.H.; Chowdhury, A.A.M.; Sharifuzzaman, S.M.; Brown, C.L.; Kwon, H.J.; Lee, E.W. A revisit to the research updates of drugs, vaccines, and bioinformatics approaches in combating COVID-19 pandemic. Front. Mol. Biosci., 2021, 7, 585899.
[http://dx.doi.org/10.3389/fmolb.2020.585899] [PMID: 33569389]
[6]
Anand, K.; Ziebuhr, J.; Wadhwani, P.; Mesters, J.R.; Hilgenfeld, R. Coronavirus main proteinase (3CLpro) structure: Basis for design of anti-SARS drugs. Science, 2003, 300(5626), 1763-1767.
[http://dx.doi.org/10.1126/science.1085658] [PMID: 12746549]
[7]
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]
[8]
V’kovski, P.; Kratzel, A.; Steiner, S.; Stalder, H.; Thiel, V. Coronavirus biology and replication: Implications for SARS-CoV-2. Nat. Rev. Microbiol., 2021, 19(3), 155-170.
[http://dx.doi.org/10.1038/s41579-020-00468-6] [PMID: 33116300]
[9]
Li, G.; De Clercq, E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat. Rev. Drug Discov., 2020, 19(3), 149-150.
[http://dx.doi.org/10.1038/d41573-020-00016-0] [PMID: 32127666]
[10]
Dai, W.; Zhang, B.; Jiang, X.M.; Su, H.; Li, J.; Zhao, Y.; Xie, X.; Jin, Z.; Peng, J.; Liu, F.; Li, C.; Li, Y.; Bai, F.; Wang, H.; Cheng, X.; Cen, X.; Hu, S.; Yang, X.; Wang, J.; Liu, X.; Xiao, G.; Jiang, H.; Rao, Z.; Zhang, L.K.; Xu, Y.; Yang, H.; Liu, H. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science, 2020, 368(6497), 1331-1335.
[11]
Hage-Melim, L.I.S.; Federico, L.B.; de Oliveira, N.K.S.; Francisco, V.C.C.; Correia, L.C.; de Lima, H.B.; Gomes, S.Q.; Barcelos, M.P.; Francischini, I.A.G.; da Silva, C.H.T.P. Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19. Life Sci., 2020, 256, 117963.
[http://dx.doi.org/10.1016/j.lfs.2020.117963] [PMID: 32535080]
[12]
Hsu, M.F.; Kuo, C.J.; Chang, K.T.; Chang, H.C.; Chou, C.C.; Ko, T.P.; Shr, H.L.; Chang, G.G.; Wang, A.H.J.; Liang, P.H. Mechanism of the maturation process of SARS-CoV 3CL protease. J. Biol. Chem., 2005, 280(35), 31257-31266.
[http://dx.doi.org/10.1074/jbc.M502577200] [PMID: 15788388]
[13]
Agostini, M.L.; Andres, E.L.; Sims, A.C.; Graham, R.L.; Sheahan, T.P.; Lu, X.; Smith, E.C.; Case, J.B.; Feng, J.Y.; Jordan, R.; Ray, A.S.; Cihlar, T.; Siegel, D.; Mackman, R.L.; Clarke, M.O.; Baric, R.S.; Denison, M.R. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio, 2018, 9(2), e00221-e18.
[http://dx.doi.org/10.1128/mBio.00221-18] [PMID: 29511076]
[14]
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.; Yang, H. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 2020, 582(7811), 289-293.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481]
[15]
Mengist, H.M.; Fan, X.; Jin, T. Designing of improved drugs for COVID-19: Crystal structure of SARS-CoV-2 main protease Mpro. Signal Transduct. Target. Ther., 2020, 5(1), 67.
[http://dx.doi.org/10.1038/s41392-020-0178-y] [PMID: 32388537]
[16]
Zhang, L.; Lin, D.; Sun, X.; Curth, U.; Drosten, C.; Sauerhering, L.; Becker, S.; Rox, K.; Hilgenfeld, R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 2020, 368(6489), 409-412.
[17]
McKee, D.L.; Sternberg, A.; Stange, U.; Laufer, S.; Naujokat, C. Candidate drugs against SARS-CoV-2 and COVID-19. Pharmacol. Res., 2020, 157, 104859.
[http://dx.doi.org/10.1016/j.phrs.2020.104859] [PMID: 32360480]
[18]
Xia, Q.; Dai, W.; Xu, K.; Ni, Q.; Li, Y.; Liu, J.; Zhao, H.; Guo, Y.; Yu, L.; Yi, P.; Su, J.; Lang, G.; Tao, J.; Shi, D.; Wu, W.; Wu, X.; Xu, Y.; Xu, M.; Yu, L.; Wang, X.; Cai, H.; Fang, Q.; Zhou, J.; Qiu, Y.; Li, L. Clinical efficacy of methylprednisolone and the combined use of lopinavir/ritonavir with arbidol in treatment of coronavirus disease 2019. J. Med. Virol., 2021, 93(7), 4446-4453.
[http://dx.doi.org/10.1002/jmv.26798] [PMID: 33448426]
[19]
Nutho, B.; Mahalapbutr, P.; Hengphasatporn, K.; Pattaranggoon, N.C.; Simanon, N.; Shigeta, Y.; Hannongbua, S.; Rungrotmongkol, T. Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? atomistic insights into the inhibitory mechanisms. Biochemistry, 2020, 59(18), 1769-1779.
[http://dx.doi.org/10.1021/acs.biochem.0c00160] [PMID: 32293875]
[20]
Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV)] in vitro. Cell Res., 2020, 30(3), 269-271.
[http://dx.doi.org/10.1038/s41422-020-0282-0] [PMID: 32020029]
[21]
Gao, J.; Tian, Z.; Yang, X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci. Trends, 2020, 14(1), 72-73.
[http://dx.doi.org/10.5582/bst.2020.01047] [PMID: 32074550]
[22]
Sen, D.; Debnath, P.; Debnath, B.; Bhaumik, S.; Debnath, S. Identification of potential inhibitors of SARS-CoV-2 main protease and spike receptor from 10 important spices through structure-based virtual screening and molecular dynamic study. J. Biomol. Struct. Dyn., 2022, 40(2), 941-962.
[http://dx.doi.org/10.1080/07391102.2020.1819883] [PMID: 32948116]
[23]
Hu, X.; Cai, X.; Song, X.; Li, C.; Zhao, J.; Luo, W.; Zhang, Q.; Ekumi, I.O.; He, Z. Possible SARS-coronavirus 2 inhibitor revealed by simulated molecular docking to viral main protease and host toll-like receptor. Future Virol., 2020, 15(6), 359-368.
[http://dx.doi.org/10.2217/fvl-2020-0099]
[24]
Ibrahim, M.A.A.; Abdelrahman, A.H.M.; Hussien, T.A.; Badr, E.A.A.; Mohamed, T.A.; El-Seedi, H.R.; Pare, P.W.; Efferth, T.; Hegazy, M.E.F. In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors. Comput. Biol. Med., 2020, 126, 104046.
[http://dx.doi.org/10.1016/j.compbiomed.2020.104046] [PMID: 33065388]
[25]
Singh, R.H.; Narsimhamurthy, K.; Singh, G. Neuronutrient impact of Ayurvedic Rasayana therapy in brain aging. Biogerontology, 2008, 9(6), 369-374.
[http://dx.doi.org/10.1007/s10522-008-9185-z] [PMID: 18931935]
[26]
Malviya, S.; Rawat, S.; Kharia, A.; Verma, M. Medicinal attributes of Acacia nilotica Linn. - A comprehensive review on ethnopharmacological claims. Int. J. of Pharm. & Life Sci., 2011, 2(6), 830-837.
[27]
Rather, L.J. Shahid-ul-Islam; Mohammad, F. Acacia nilotica (L.): A review of its traditional uses, phytochemistry, and pharmacology. Sustain. Chem. Pharm., 2015, 2(December), 12-30.
[http://dx.doi.org/10.1016/j.scp.2015.08.002]
[28]
Li, Y.; Xie, S.; Ying, J.; Wei, W.; Gao, K. Chemical structures of lignans and neolignans isolated from lauraceae. Molecules, 2018, 23(12), 3164.
[http://dx.doi.org/10.3390/molecules23123164] [PMID: 30513687]
[29]
Ni, G.; Shi, G.R.; Zhang, D.; Fu, N.J.; Yang, H.Z.; Chen, X.G.; Yu, D.Q. Cytotoxic lignans and sesquiterpenoids from the rhizomes of Acorus tatarinowii. Planta Med., 2016, 82(7), 632-638.
[http://dx.doi.org/10.1055/s-0035-1568248] [PMID: 26848706]
[30]
Pastorino, G.; Cornara, L.; Soares, S.; Rodrigues, F.; Oliveira, M.B.P.P. Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother. Res., 2018, 32(12), 2323-2339.
[http://dx.doi.org/10.1002/ptr.6178] [PMID: 30117204]
[31]
Dastagir, G.; Rizvi, M.A. Review - Glycyrrhiza glabra L. (Liquorice). Pak. J. Pharm. Sci., 2016, 29(5), 1727-1733.
[PMID: 27731836]
[32]
Ito, H.; Yamaguchi, K.; Kim, T.H.; Khennouf, S.; Gharzouli, K.; Yoshida, T. Dimeric and trimeric hydrolyzable tannins from Quercus coccifera and Quercus suber. J. Nat. Prod., 2002, 65(3), 339-345.
[http://dx.doi.org/10.1021/np010465i] [PMID: 11908975]
[33]
Şöhretoğlu, D.; Kuruüzüm-Uz, A.; Simon, A.; Patocs, T.; Dekany, M. New secondary metabolites from Quercus coccifera L. Rec. Nat. Prod., 2014, 8, 323-329.
[34]
Bag, A.; Bhattacharyya, S.K.; Chattopadhyay, R.R. The development of Terminalia chebula Retz. (Combretaceae) in clinical research. Asian Pac. J. Trop. Biomed., 2013, 3(3), 244-252.
[http://dx.doi.org/10.1016/S2221-1691(13)60059-3] [PMID: 23620847]
[35]
Upadhyay, S.; Tripathi, P.K.; Singh, M.; Raghavendhar, S.; Bhardwaj, M.; Patel, A.K. Evaluation of medicinal herbs as a potential therapeutic option against SARS‐CoV‐2 targeting its main protease. Phytother. Res., 2020, 34(12), 3411-3419.
[http://dx.doi.org/10.1002/ptr.6802] [PMID: 32748969]
[36]
Hossen, K.; Das, K.R.; Okada, S.; Iwasaki, A.; Suenaga, K.; Kato-Noguchi, H. Allelopathic potential and active substances from Wedelia Chinensis (Osbeck). Foods, 2020, 9(11), 1591.
[http://dx.doi.org/10.3390/foods9111591] [PMID: 33147830]
[37]
Koul, S.; Pandurangan, A.; Khosa, R.L. Wedelia chinenis (Asteraceae)-An overview. Asian Pac. J. Trop. Biomed., 2012, 2(2)(Suppl.), S1169-S1175.
[http://dx.doi.org/10.1016/S2221-1691(12)60380-3]
[38]
Trott, O.; Olson, A.J. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2009, 31(2)
[http://dx.doi.org/10.1002/jcc.21334]
[39]
Krieger, E.; Vriend, G.; Kelso, J. YASARA View-molecular graphics for all devices-from smartphones to workstations. Bioinformatics, 2014, 30(20), 2981-2982.
[http://dx.doi.org/10.1093/bioinformatics/btu426] [PMID: 24996895]
[40]
Yuan, S.; Chan, H.C.S.; Hu, Z. Using PYMOL as a platform for computational drug design. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2017, 7(2), e1298.
[http://dx.doi.org/10.1002/wcms.1298]
[41]
Mark, P.; Nilsson, L. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J. Phys. Chem. A, 2001, 105(43), 9954-9960.
[http://dx.doi.org/10.1021/jp003020w]
[42]
Jorgensen, W.L.; Maxwell, D.S.; Tirado-Rives, J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc., 1996, 118(45), 11225-11236.
[http://dx.doi.org/10.1021/ja9621760]
[43]
Douglas, A.G.; Emily, A.C. Time-reversible multiple time scale ab initio molecular dynamics. J. Phys. Chem., 1993, 97(51), 13429-13434.
[http://dx.doi.org/10.1021/j100153a002]
[44]
Cheng, A.; Merz, K.M. Application of the nosé−hoover chain algorithm to the study of protein dynamics. J. Phys. Chem., 1996, 100(5), 1927-1937.
[http://dx.doi.org/10.1021/jp951968y]
[45]
Kalibaeva, G.; Ferrario, M.; Ciccotti, G. Constant pressure-constant temperature molecular dynamics: A correct constrained NPT ensemble using the molecular virial. Mol. Phys., 2003, 101(6), 765-778.
[http://dx.doi.org/10.1080/0026897021000044025]
[46]
Kumar, B.K. Faheem; Sekhar, K.V.G.C.; Ojha, R.; Prajapati, V.K.; Pai, A.; Murugesan, S. Pharmacophore based virtual screening, molecular docking, molecular dynamics and MM-GBSA approach for identification of prospective SARS-CoV-2 inhibitor from natural product databases. J. Biomol. Struct. Dyn., 2022, 40(3), 1363-1386.
[http://dx.doi.org/10.1080/07391102.2020.1824814] [PMID: 32469279]
[47]
Karan, K.B.; Faheem; Balana, F.R.; Melcon-Fernandez, E.; Perez-Pertejo Yolanda, Y.; Reguera, R.M.; Adinarayana, N.; Chandra, S.K.V.G.; Vanaparthi, S.; Murugesan, S. Design, synthesis and evaluation of novel β-carboline ester analogues as potential antileishmanial agents. J. Biomol. Struct. Dyn., 2021, 1-16.
[http://dx.doi.org/10.1080/07391102.2021.1973564]
[48]
Jayaram, B.; Singh, T.; Mukherjee, G.; Mathur, A.; Shekhar, S.; Shekhar, V. Sanjeevini: A freely accessible web-server for target directed lead molecule discovery. BMC Bioinformatics, 2012, 13(S17)(Suppl. 17), S7.
[http://dx.doi.org/10.1186/1471-2105-13-S17-S7] [PMID: 23282245]
[49]
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]

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