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ISSN (Print): 2666-7967
ISSN (Online): 2666-7975

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Research Article

An In-silico Multi-Targeted Approach in Search of Potential Drug Candidate( s) Against SARS-CoV-2 Lung Infection

Author(s): Kapish Kapoor, Vishnu Das, Ayushi Bhatnagar, Sunita Panchawat and Joohee Pradhan*

Volume 3, Issue 6, 2022

Published on: 21 December, 2022

Article ID: e021222211552 Pages: 14

DOI: 10.2174/2666796704666221202143702

Abstract

Background: The multitargeted computational approach for the design of drugs to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung infection from herbal sources may lead to compound(s) that is/are safe (derived from natural sources), effective (act on predefined targets) and broad spectrum (active in both, adult and juvenile population).

Objective: The present work aims at developing a specific and effective treatment for a lung infection in both the adult and juvenile population, caused due to SARS-CoV-2 through a computational approach.

Methods: A systematic virtual screening of 27 phytoconstituents from 11 Indian herbs with antiviral, antiinflammatory, and immunomodulatory activity was performed. After applying the Lipinski rule of five, 19 compounds that fitted well were subjected to molecular docking studies using Molegro virtual docker 6.0 with two targets viz. SARS-CoV-2 main protease (Mpro) (PDB ID 6LU7) and ACE receptor (PDB ID 6M0J). The best-docked complexes were used to develop a merged feature pharmacophore using Ligandscout software, to know the structural requirements to develop multitarget inhibitor(s) of SARS-CoV- 2. Drug likeliness and ADMET studies were also performed.

Results: The results revealed that Syringin, a glycoside from Tinospora cordifolia, has a good binding affinity towards both targets as compared to Remdesivir. Furthermore, drug likeliness and ADMET studies established its better bioavailability and low toxicity.

Conclusion: The pharmacophores developed from protein-ligand complexes provided an important understanding to design multitarget inhibitor(s) of SARS-CoV-2 to treat COVID-19 lung infection in both the adult and juvenile populations. Syringin may be subjected to further wet-lab studies to establish the results obtained through in-silico studies.

Keywords: SARS-CoV-2, COVID-19 lung infection, molecular docking, multi-target inhibitor, Syringin, Tinospora cordifolia, phytoconstituents.

Graphical Abstract

[1]
Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020; 55(3): 105924-4.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105924] [PMID: 32081636]
[2]
Sahasranaman A, Kumar N. Network structure of COVID-19 spread and the lacuna in India’s testing strategy Quantit Biol. 2020. Available from: https://arxiv.org/ftp/arxiv/papers/2003/2003.09715.pdf
[3]
Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020; 5(4): 562-9.
[http://dx.doi.org/10.1038/s41564-020-0688-y] [PMID: 32094589]
[4]
Channappanavar R, Perlman S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39(5): 529-39.
[http://dx.doi.org/10.1007/s00281-017-0629-x] [PMID: 28466096]
[5]
Jena NR. Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2. Chem Phys Impact 2021; 2: 100011.
[http://dx.doi.org/10.1016/j.chphi.2021.100011]
[6]
Medhi B, Prajapat M, Sarma P, et al. Drug for coronavirus: A systematic review. Indian J Pharmacol 2020; 52(1): 56-65.
[http://dx.doi.org/10.4103/ijp.IJP_115_20] [PMID: 32201449]
[7]
Arif MN. Catechin Derivatives as Inhibitor of COVID-19 main protease (Mpro): Molecular docking studies unveil an opportunity against CORONA. Comb Chem High Throughput Screen 2021; 25(1): 197-203.
[http://dx.doi.org/10.2174/1871520620666201123101002] [PMID: 33231155]
[8]
Joshi T, Sharma P, Joshi T, Pundir H, Mathpal S, Chandra S. Structure-based screening of novel lichen compounds against SARS Coronavirus main protease (Mpro) as potentials inhibitors of COVID-19. Mol Divers 2021; 25(3): 1665-77.
[http://dx.doi.org/10.1007/s11030-020-10118-x] [PMID: 32602074]
[9]
Lokhande KB, Doiphode S, Vyas R, Swamy KV. Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals mitoxantrone, leucovorin, birinapant, and dynasore as potent drugs against COVID-19. J Biomol Struct Dyn 2021; 39(18): 7294-305.
[http://dx.doi.org/10.1080/07391102.2020.1805019] [PMID: 32815481]
[10]
Jin Z, Du X, Xu Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582(7811): 289-93.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481]
[11]
Chen J. Pathogenicity and transmissibility of 2019-nCoV-A quick overview and comparison with other emerging viruses. Microbes Infect 2020; 22(2): 69-71.
[http://dx.doi.org/10.1016/j.micinf.2020.01.004] [PMID: 32032682]
[12]
Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med 2020; 382(24): 2327-36.
[http://dx.doi.org/10.1056/NEJMoa2007016] [PMID: 32275812]
[13]
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395(10236): 1569-78.
[http://dx.doi.org/10.1016/S0140-6736(20)31022-9] [PMID: 32423584]
[14]
Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B 2020; 10(5): 766-88.
[http://dx.doi.org/10.1016/j.apsb.2020.02.008] [PMID: 32292689]
[15]
Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016; 79(3): 629-61.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055] [PMID: 26852623]
[16]
Arora R, Chawla R, Marwah R, et al. Potential of complementary and alternative medicine in preventive management of novel H1N1 Flu (Swine Flu) pandemic: Thwarting potential disasters in the bud. Evid Based Complement Alternat Med 2011; 2011: 586506.
[17]
Zimmermann P, Curtis N. Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the agerelated difference in severity of SARS-CoV-2 infections. Arch Dis Child 2020. archdischild-2020-320338.
[PMID: 33262177]
[18]
Golechha M. Time to realise the true potential of Ayurveda against COVID-19. Brain Behav Immun 2020; 87: 130-1.
[http://dx.doi.org/10.1016/j.bbi.2020.05.003] [PMID: 32389701]
[19]
Niphade SR, Asad M, Chandrakala GK, Toppo E, Deshmukh P. Immunomodulatory activity of Cinnamomum zeylanicum bark. Pharm Biol 2009; 47(12): 1168-73.
[http://dx.doi.org/10.3109/13880200903019234]
[20]
Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: From ancient medicine to current clinical trials. Cell Mol Life Sci 2008; 65(11): 1631-52.
[http://dx.doi.org/10.1007/s00018-008-7452-4] [PMID: 18324353]
[21]
Mohan L, Amberkar M, Kumari MJ. Ocimum sanctum Linn. (TULSI)-An overview. Int J Pharm Sci Rev Res 2011; 7(1): 51-3.
[22]
Vardhan S, Sahoo SK. In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19. Comput Biol Med 2020; 124: 103936-6.
[http://dx.doi.org/10.1016/j.compbiomed.2020.103936] [PMID: 32738628]
[23]
Soutar DA, Doucette CD, Liwski RS, Hoskin DW. Piperine, a pungent alkaloid from black pepper, inhibits B lymphocyte activation and effector functions. Phytother Res 2017; 31(3): 466-74.
[http://dx.doi.org/10.1002/ptr.5772] [PMID: 28102026]
[24]
Salehi B, Zakaria ZA, Gyawali R, et al. Piper species: A comprehensive review on their phytochemistry, biological activities and applications. Molecules 2019; 24(7): 1364.
[http://dx.doi.org/10.3390/molecules24071364] [PMID: 30959974]
[25]
Sultana S, Khan A, Safhi MM, Alhazmi HA. Cough suppressant herbal drugs: A review. Int J Pharm Sci Invent 2016; 5: 15-28.
[26]
Ratha K, Sahu S, Sathya K, Sabu I, Rao M. Ayurveda management of alcoholic liver disease with acute hepatitis B: A case report. J Ayurveda Case Reports 2020; 3(4): 143.
[http://dx.doi.org/10.4103/jacr.jacr_63_20]
[27]
Gangwar AK, Ghosh AK. Medicinal uses and pharmacological activity of Adhatoda vasica. Int J Herb Med 2014; 2(1): 88-91.
[28]
Farooqi A, Singh VP, Kumar SJ. Spices; Plants, M., Bhumyamalaki: an anti jaundice plant. Indian J Arecanut Spices Med Plants 2000; 2(3): 86-7.
[29]
Govind P. Medicinal plants against liver diseases. Int J Pharm 2011; 2(5): 115-21.
[30]
Patel JJ, Acharya SR, Acharya NS. Clerodendrum serratum (L.) Moon. A review on traditional uses, phytochemistry and pharmacological activities. J Ethnopharmacol 2014; 154(2): 268-85.
[http://dx.doi.org/10.1016/j.jep.2014.03.071] [PMID: 24727551]
[31]
Patel K, Shah N, Gupta SN. Effect of Ayurvedic management in 130 patients of diabetic nephropathy. Ayu 2011; 32(1): 55-8.
[http://dx.doi.org/10.4103/0974-8520.85727] [PMID: 22131758]
[32]
Dalvi YV. The comprehensive review on kantakari plant. Asian J Pharm Sci 2018; 8(3): 140-4.
[http://dx.doi.org/10.5958/2231-5659.2018.00025.5]
[33]
Tekuri SK, Pasupuleti SK, Konidala KK, Amuru SR, Bassaiahgari P, Pabbaraju NJ. Phytochemical and pharmacological activities of Solanum surattense Burm. f.–A review. J Appl Pharm Sci 2019; 9(3): 126-36.
[http://dx.doi.org/10.7324/JAPS.2019.90318]
[34]
Dalavi CM, Ghatge SR, Dixit GB. Solanum: A valuable genus of sacred groves, Sacred groves-from tradition to conservation. The proceedings of UGC sponsored National Conference on “Sacred groves as a repository for Ethnomedicinal plants” organized by Department of Botany, Rajaram College, Kolhapur 2013; 24-33.
[35]
Gupta P, Parashar AK, Nema RK. Extraction and standardization of anthelmintic activity of Solanum xanthocarpum. Curr Res Pharm Sci 2013; pp. 45-7.
[36]
Han X, Parker TL. Anti-inflammatory activity of clove (Eugenia caryophyllata) essential oil in human dermal fibroblasts. Pharm Biol 2017; 55(1): 1619-22.
[http://dx.doi.org/10.1080/13880209.2017.1314513] [PMID: 28407719]
[37]
Ayushi UA, Danish SM, Mohammad UP. A review on biological and therapeutic uses of Syzygium aromaticum Linn. (Clove): Based on phyto-chemistry and pharmacological evidences. Int J Botany Stud 2020; 5(4): 33-9.
[38]
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361(9374): 2045-6.
[http://dx.doi.org/10.1016/S0140-6736(03)13615-X] [PMID: 12814717]
[39]
Curreli F, Friedman-Kien AE, Flore O. Glycyrrhizic acid alters Kaposi sarcoma-Associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes. J Clin Invest 2005; 115(3): 642-52.
[http://dx.doi.org/10.1172/JCI200523334] [PMID: 15765147]
[40]
Kharisma VD, Septiadi L, Syafrudin S. Prediction of novel bioactive compound from Zingiber officinale as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 through computational study. Bioinform Viomed Res J 2018; 1(2): 49-55.
[41]
Raghavendhar S, Tripati PK, Ray P, Patel AK. Evaluation of medicinal herbs for Anti-CHIKV activity. Virology 2019; 533: 45-9.
[http://dx.doi.org/10.1016/j.virol.2019.04.007] [PMID: 31082733]
[42]
Kumar Verma A, Kumar V, Singh S, et al. Repurposing potential of Ayurvedic medicinal plants derived active principles against SARS-CoV-2 associated target proteins revealed by molecular docking, molecular dynamics and MM-PBSA studies. Biomed Pharmacother 2021; 137: 111356.
[http://dx.doi.org/10.1016/j.biopha.2021.111356] [PMID: 33561649]
[43]
RCSB Protein Data Bank (RCSB PDB). Available from: https://www.rcsb.org/
[44]
Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581(7807): 215-20.
[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[45]
SAVESv6.0 - Structure Validation Server. Available from: https://saves.mbi.ucla.edu/results?job=715968&p=procheck
[46]
Keretsu S, Bhujbal SP, Cho SJ. Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. Sci Rep 2020; 10(1): 17716.
[http://dx.doi.org/10.1038/s41598-020-74468-0] [PMID: 33077821]
[47]
Patel A, Rajendran M, Shah A, Patel H, Pakala SB, Karyala P. Virtual screening of curcumin and its analogs against the spike surface glycoprotein of SARS-CoV-2 and SARS-CoV. J Biomol Struct Dyn 2021; •••: 1-9.
[PMID: 33397223]
[48]
Molegro Virtual Docker. Available from: http://molexus.io/molegro-virtual-docker/
[49]
Thomsen R, Christensen MH. MolDock: A new technique for high-accuracy molecular docking. J Med Chem 2006; 49(11): 3315-21.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[50]
Gehlhaar DK, Verkhivker GM, Rejto PA, et al. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: Conformationally flexible docking by evolutionary programming. Chem Biol 1995; 2(5): 317-24.
[http://dx.doi.org/10.1016/1074-5521(95)90050-0] [PMID: 9383433]
[51]
Yang JM, Chen CC. GEMDOCK: A generic evolutionary method for molecular docking. Proteins 2004; 55(2): 288-304.
[http://dx.doi.org/10.1002/prot.20035] [PMID: 15048822]
[52]
Naeem S, Hylands P, Barlow DJ. Docking studies of chlorogenic acid against aldose redutcase by using molgro virtual docker software. J Appl Pharm Sci 2013; 3(1): 13.
[53]
Nisha CM, Kumar A, Nair P, et al. Molecular docking and in silico ADMET study reveals acylguanidine 7a as a potential inhibitor of β-secretase. Adv Bioinforma 2016; 2016: 1-6.
[http://dx.doi.org/10.1155/2016/9258578] [PMID: 27190510]
[54]
PreADMET. Available from: http://preadmet.bmdrc.org/
[55]
Wolber G, Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model 2005; 45(1): 160-9.
[http://dx.doi.org/10.1021/ci049885e] [PMID: 15667141]
[56]
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1-3): 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[57]
Di L, Kerns E, Carter G. Drug-like property concepts in pharmaceutical design. Curr Pharm Des 2009; 15(19): 2184-94.
[http://dx.doi.org/10.2174/138161209788682479] [PMID: 19601822]
[58]
Saurav K, Zhang W, Saha S, et al. In silico molecular docking, preclinical evaluation of spiroindimicins A-D, lynamicin A and D isolated from deep marine sea derived Streptomyces sp. SCSIO 03032. Interdiscip Sci 2014; 6(3): 187-96.
[http://dx.doi.org/10.1007/s12539-013-0200-y] [PMID: 25205496]
[59]
Zhao YH, Le J, Abraham MH, et al. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-Activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci 2001; 90(6): 749-84.
[http://dx.doi.org/10.1002/jps.1031] [PMID: 11357178]
[60]
Foti RS, Wahlstrom JL. CYP2C19 inhibition: The impact of substrate probe selection on in vitro inhibition profiles. Drug Metab Dispos 2008; 36(3): 523-8.
[http://dx.doi.org/10.1124/dmd.107.019265] [PMID: 18048485]
[61]
Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A. Molecular genetics of CYP2D6: Clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002; 53(2): 111-22.
[http://dx.doi.org/10.1046/j.0306-5251.2001.01548.x] [PMID: 11851634]
[62]
Dai D, Tang J, Rose R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 2001; 299(3): 825-31.
[PMID: 11714865]
[63]
Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 2013; 61(25): 2495-502.
[http://dx.doi.org/10.1016/j.jacc.2013.02.058] [PMID: 23563132]
[64]
Mitragotri S, Anissimov YG, Bunge AL, et al. Mathematical models of skin permeability: An overview. Int J Pharm 2011; 418(1): 115-29.
[http://dx.doi.org/10.1016/j.ijpharm.2011.02.023] [PMID: 21356301]
[65]
Danker T, Möller C. Early identification of hERG liability in drug discovery programs by automated patch clamp. Front Pharmacol 2014; 5: 203.
[http://dx.doi.org/10.3389/fphar.2014.00203] [PMID: 25228880]
[66]
Ames BN, Gurney EG, Miller JA, Bartsch H. Carcinogens as frameshift mutagens: metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens. Proc Natl Acad Sci USA 1972; 69(11): 3128-32.
[http://dx.doi.org/10.1073/pnas.69.11.3128] [PMID: 4564203]

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