Withania somnifera phytochemicals possess SARS-CoV-2 RdRp and human TMPRSS2 protein binding potential

*Article not assigned to an issue yet

, , , , , , , , ,


Research Articles | Published:

Print ISSN : 0970-4078.
Online ISSN : 2229-4473.
Website:www.vegetosindia.org
Pub Email: contact@vegetosindia.org
Doi: 10.1007/s42535-022-00404-4
First Page: 0
Last Page: 0
Views: 142


Keywords: SARS-CoV-2, Withania somnifera , Phytochemical, TMPRSS2, RNA dependent RNA polymerase


Abstract


Coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has infected approximately 26 million people and caused more than 6 million deaths globally. Spike (S)-protein on the outer surface of the virus uses human trans-membrane serine protease-2 (TMPRSS2) to gain entry into the cell. Recent reports indicate that human dipeptidyl peptidase-4 inhibitors (DPP4 or CD26) could also be utilized to check the S-protein mediated viral entry into COVID-19 patients. RNA dependent RNA polymerase (RdRp) is another key virulence protein of SARS-CoV-2 life cycle. The study aimed to identify the potential anti-SARS-CoV-2 inhibitors present in Withania somnifera (Solanaceae) using computer aided drug discovery approach. Molecular docking results showed that flavone glycoside, sugar alcohol, and flavonoid present in W. somnifera showed − 11.69, − 11.61, − 10.1, − 7.71 kcal/mole binding potential against S-protein, CD26, RdRp, and TMPRSS2 proteins. The major standard inhibitors of the targeted proteins (Sitagliptin, VE607, Camostat mesylate, and Remdesivir) showed the − 7.181, − 6.6, − 5.146, and − 7.56 kcal/mole binding potential. Furthermore, the lead phytochemicals and standard inhibitors bound and non-bound RdRp and TMPRSS2 proteins were subjected to molecular dynamics (MD) simulation to study the complex stability and change in protein conformation. The result showed energetically favorable and stable complex formation in terms of RMSD, RMSF, SASA, Rg, and hydrogen bond formation. Drug likeness and physiochemical properties of the test compounds exhibited satisfactory results. Taken together, the present study suggests the presence of potential anti-SARS-CoV-2 phytochemicals in W. somnifera that requires further validation in in vitro and in vivo studies.

SARS-CoV-2, 
              Withania somnifera
            , Phytochemical, TMPRSS2, RNA dependent RNA polymerase


References


Berger JP, SinhaRoy R, Pocai A, Kelly TM, Scapin G, Gao YD, Pryor KAD, Wu JK, Eiermann GJ, Xu SS, Zhang X, Tatosian DA, Weber AE, Thornberry NA, Carr RD (2017) A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice. Endocrinol Diabetes Metab 1:1–8. https://doi.org/10.1002/edm2.2


Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242. https://doi.org/10.1093/nar/28.1.235


Cai Z, Zhang G, Tang B, Liu Y, Fu X, Zhang X (2015) Promising Anti-influenza Properties of Active Constituent of Withania somnifera Ayurvedic Herb in Targeting Neuraminidase of H1N1 Influenza: Computational Study. Cell Biochem Biophys 72:727–739. https://doi.org/10.1007/s12013-015-0524-9


Casrouge A, Sauer AV, Barreira da Silva R, Tejera-Alhambra M, Sánchez-Ramón S, ICAReB, Cancrini C, Ingersoll MA, Aiuti A, Albert ML (2018) Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4. Clin Exp Immunol 194:166–179. https://doi.org/10.1111/cei.13163


Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:1–13. https://doi.org/10.1038/srep42717


Dallakyan S (2008) PyRx-python prescription v. 0.8. The Scripps Research Institute. 2008; 2010


Das S, Sarmah S, Lyndem S, Singha Roy A (2021) An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study. J Biomol Struct Dyn 39:3347–3357. https://doi.org/10.1080/07391102.2020.1763201


Duke JA (1992) Database of phytochemical constituents of GRAS herbs and other economic plants. CRC Press, Boca Raton


El Khatabi K, Aanouz I, El-Mernissi R, Singh AK, Ajana MA, Lakhlifi T, Kumar S, Bouachrine M (2021) Integrated 3D-QSAR, molecular docking, and molecular dynamics simulation studies on 1,2,3-triazole based derivatives for designing new acetylcholinesterase inhibitors. Turk J Chem 45:647–660. https://doi.org/10.3906/kim-2010-34


Ezebuo FC, Kushwaha PP, Singh AK, Kumar S, Singh P (2019) In-silico methods of drug design: molecular simulations and free energy calculations. In: Kumar S, Egbuna C (eds) Phytochemistry: an in-silico and in-vitro update 2019. Springer, Singapore, pp 521–533


Ganguly B, Umapathi V, Rastogi SK (2018) Nitric oxide induced by Indian ginseng root extract inhibits Infectious Bursal Disease virus in chicken embryo fibroblasts in vitro. J Anim Sci Technol 60:1–5. https://doi.org/10.1186/s40781-017-0156-2


Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M (2020) The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 295:4773–4779. https://doi.org/10.1074/jbc.AC120.013056


Gupta S, Singh AK, Kushwaha PP, Prajapati KS, Shuaib M, Senapati S, Kumar S (2021a) Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies. J Biomol Struct Dyn 39:4334–4345. https://doi.org/10.1080/07391102.2020.1776157


Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181:271–280. https://doi.org/10.1016/j.cell.2020.02.052


Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N (2019) TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol 93:1–15. https://doi.org/10.1128/JVI.01815-18


Jain J, Narayanan V, Chaturvedi S, Pai S, Sunil S (2018) In vivo evaluation of Withania somnifera-based Indian traditional formulation (Amukkara Choornam), against Chikungunya virus-induced morbidity and arthralgia. J Evid Based Integr Med 23:11–25. https://doi.org/10.1177/2156587218757661


Kempegowda PK, Zameer F, Narasimashetty CK, Kollur SP, Murari SK (2018) Inhibitory potency of Withania somnifera extracts against DPP-4: an in vitro evaluation. Afr J Tradit Complement Altern Med 15:11–25. https://doi.org/10.21010/ajtcam.v15i1.2


Kim SC, Schneeweiss S, Glynn RJ, Doherty M, Goldfine AB, Solomon DH (2015) Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study. Ann Rheum Dis 74:1968–1975. https://doi.org/10.1136/annrheumdis-2014-205216


Kumar G, Patnaik R (2016) Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: an in silico study. Med Hypotheses 92:35–43. https://doi.org/10.1016/j.mehy.2016.04.034


Kumar S, Kushwaha PP, Gupta S (2019) Emerging targets in cancer drug resistance. Cancer Drug Resist. https://doi.org/10.20517/cdr.2018.27. 2:161 – 77


Kushwaha PP, Vardhan PS, Kapewangolo P, Shuaib M, Prajapati SK, Singh AK, Kumar S (2019) Bulbine frutescens phytochemical inhibits notch signaling pathway and induces apoptosis in triple negative and luminal breast cancer cells. Life Sci 234:1–15. https://doi.org/10.1016/j.lfs.2019.116783


Kushwaha PP, Singh AK, Bansal T, Yadav A, Prajapati KS, Shuaib M, Kumar S (2020) Identification of natural inhibitors against SARS-CoV-2 Drugable targets using molecular docking, molecular dynamics Simulation, and MM-PBSA approach. Front Cell Infect Microbiol 11:1–17. https://doi.org/10.3389/fcimb.2021.730288


Kushwaha PP, Singh AK, Prajapati KS, Shuaib M, Fayez S, Bringmann G, Kumar S (2020a) Induction of apoptosis in breast cancer cells by naphthylisoquinoline alkaloids. Toxicol Appl Pharmacol 409:1–12. https://doi.org/10.1016/j.taap.2020.115297


Kushwaha PP, Singh AK, Shuaib M, Prajapati KS, Vardhan PS, Gupta S, Kumar S (2020b) 3-O-(E)-p-Coumaroyl betulinic acid possess anticancer activity and inhibit Notch signaling pathway in breast cancer cells and mammosphere. Chem Biol Interact 328:1–12. https://doi.org/10.1016/j.cbi.2020.109200


Kushwaha PP, Kumar R, Neog PR, Behara MR, Singh P, Kumar A, Prajapati KS, Singh AK, Shuaib M, Sharma AK, Pandey AK (2021b) Characterization of phytochemicals and validation of antioxidant and anticancer activity in some Indian polyherbal ayurvedic products. Vegetos 2021 34:286–299. https://doi.org/10.1007/s42535-021-00205-1


Kushwaha PP, Maurya SK, Singh A, Prajapati KS, Singh AK, Shuaib M, Kumar S (2021a) Bulbine frutescens phytochemicals as novel ABC-transporter inhibitor: a molecular docking and molecular dynamics simulation study. J Cancer Metastasis Treat 7:1–13. https://doi.org/10.20517/2394-4722.2020.92


Kushwaha PP, Singh AK, Prajapati KS, Shuaib M, Gupta S, Kumar S (2021) Phytochemicals present in Indian ginseng possess potential to inhibit SARS-CoV-2 virulence: a molecular docking and MD simulation study. Microb Pathog 157:1–11. https://doi.org/10.1016/j.micpath.2021.104954


Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778–2786. https://doi.org/10.1021/ci200227u


Li Y, But PP, Ooi VE (2005) Antiviral activity and mode of action of caffeoylquinic acids from Schefflera heptaphylla (L.) Frodin. Antiviral Res 68:1–9. https://doi.org/10.1016/j.antiviral.2005.06.004


Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF (2013) Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature 500:227–231. https://doi.org/10.1038/nature12328


Maurya SK, Maurya AK, Mishra N, Siddique HR (2020) Virtual screening, ADME/T, and binding free energy analysis of anti-viral, anti-protease, and anti-infectious compounds against NSP10/NSP16 methyltransferase and main protease of SARS CoV-2. J Recept Signal Transduct Res 40:605–612. https://doi.org/10.1080/10799893.2020.1772298


Mundkinajeddu D, Sawant LP, Koshy R, Akunuri P, Singh VK, Mayachari A, Sharaf MH, Balasubramanian M, Agarwal A (2014) Development and validation of high performance liquid chromatography method for simultaneous estimation of flavonoid glycosides in Withania somnifera aerial parts. Int Sch Res Notices 2014:1–6. https://doi.org/10.1155/2014/351547


Nagarajan N, Yapp EKY, Le NQK, Yeh HY (2019) In silico screening of sugar alcohol compounds to inhibit viral matrix protein VP40 of Ebola virus. Mol Biol Rep 46:3315–3324. https://doi.org/10.1007/s11033-019-04792-w


Naveed M, Hejazi V, Abbas M, Kamboh AA, Khan GJ, Shumzaid M, Ahmad F, Babazadeh D, FangFang X, Modarresi-Ghazani F, WenHua L, XiaoHui Z (2018) Chlorogenic acid (CGA): a pharmacological review and call for further research. Biomed Pharmacother 97:67–74. https://doi.org/10.1016/j.biopha.2017.10.064


O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) Open Babel: an open chemical toolbox. J Cheminform 3:1–14. https://doi.org/10.1186/1758-2946-3-33


Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084


Schüttelkopf AW, van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60:1355–1363. https://doi.org/10.1107/S0907444904011679


Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, Bilia AR, Efferth T, Schwarz W (2014) Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med 80:177–182. https://doi.org/10.1055/s-0033-1360277


Senapati S, Kumar S, Singh AK, Banerjee P, Bhagavatula S (2020) Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human. J Genet 99:1–5. https://doi.org/10.1007/s12041-020-01217-7


Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F (2020) Structural basis of receptor recognition by SARS-CoV-2. Nature 581:221–224. https://doi.org/10.1038/s41586-020-2179-y


Singh V, Singh B, Sharma A, Kaur K, Gupta AP, Salar RK, Hallan V, Pati PK (2017) Leaf spot disease adversely affects human health-promoting constituents and withanolide biosynthesis in Withania somnifera (L.) Dunal. J Appl Microbiol 122:153–165. https://doi.org/10.1111/jam.13314


Singh AK, Kushwaha PP, Prajapati KS, Shuaib M, Gupta S, Kumar S (2020) Identification of FDA approved drugs and nucleoside analogues as potential SARS-CoV-2 A1pp domain inhibitor: an in silico study. Comput Biol Med 130:1–10. https://doi.org/10.1016/j.compbiomed.2020.104185


Singh AK, Patel PK, Choudhary K, Joshi J, Yadav D, Jin JO (2020b) Quercetin and Coumarin Inhibit Dipeptidyl Peptidase-IV and Exhibits Antioxidant Properties: In Silico, In Vitro, Ex Vivo. Biomolecules 10:1–14. https://doi.org/10.3390/biom1002020b7


Singh AK, Shuaib M, Kushwaha PP, Prajapati KS, Sharma R, Kumar S (2021) In silico updates on lead identification for obesity and cancer. In: Kumar S, Gupta S (eds) Obesity and Cancer. Springer, Singapore, pp 257–277


Solerte SB, Di Sabatino A, Galli M, Fiorina P (2020) Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19. Acta Diabetol 57:779–783. https://doi.org/10.1007/s00592-020-01539-z


Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461. https://doi.org/10.1002/jcc.21334


Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. https://doi.org/10.1002/jcc.20291


Vankadari N, Wilce JA (2020) Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect 9:601–604. https://doi.org/10.1080/22221751.2020.1739565


Verma AK, Maurya SK, Kumar A, Barik M, Yadav V, Umar B, Lawal M, Usman ZA, Adam MA, Awal B (2020) Inhibition of multidrug resistance property of Candida albicans by natural compounds of parthenium hysterophorus L. An in-silico approach. J Pharmacogn Phytochem 9:55–64. https://doi.org/10.22271/phyto.2020.v9.i3a.11480


Waseem M, Ahmad MK, Srivatava VK, Rastogi N, Serajuddin M, Kumar S, Mishra DP, Sankhwar SN, Mahdi AA (2017) Evaluation of miR-711 as novel biomarker in prostate cancer progression. Asian Pac J Cancer Prev 18:2185–2191. https://doi.org/10.22034/APJCP.2017.18.8.2185


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 (2020) Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B 10:766–788. https://doi.org/10.1016/j.apsb.2020.02.008

 


Acknowledgements



Author Information


Prajapati Kumari Sunita
Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, India

Singh Atul Kumar
Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, India


Kushwaha Prem Prakash
Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, India


Shuaib Mohd
Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, India


Maurya Santosh Kumar
Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, India

Gupta Sanjay
Department of Urology, Case Western Reserve University, Cleveland, USA

Senapati Sabyasachi
Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India

,
Singh Surya Pratap
Department of Bioscience and Biotechnology, Bansthali Vidyapith, Banasthali, India

Waseem Mohammad
Department of Zoology, Jagdam College, Jai Prakash University, Chapra, India

Kumar Shashank
Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, India