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Research Article Section: Pharmacology

In silico Study of Some Dexamethasone Analogs and Derivatives against SARs-CoV-2 Target: A Cost-effective Alternative to Remdesivir for Various COVID Phases

Author(s): Ruchi Pandey, Itishree Dubey, Iqrar Ahmad, Debarshi Kar Mahapatra, Harun Patel and Pranesh Kumar*

Volume 2, Issue 4, 2022

Published on: 12 May, 2022

Page: [294 - 309] Pages: 16

DOI: 10.2174/2210298102666220404102217

Abstract

Aim: The black market for Remdesivir for the treatment of COVID-19 is surging in the world. This condition leads to the uprising of drugs from the common hospital inventory, of which Dexamethasone is an effective weapon to be employed against the coronavirus. Background: Remdesivir is an intravenous nucleotide prodrug of an adenosine analog. Dexamethasone was tested in hospitalized patients with COVID-19 in the UK’s national clinical trial and was found to benefit critically ill patients. Therefore, it could be a better alternative.

Objective: A computational approach of molecular docking was performed to determine the binding interactions ability between the selected 3D-models of COVID-19 protease and inflammatory targets with suggested modified ligand compounds through Autodock v.1.5.6 software that also establishes the plausible mechanism.

Methods: Dexamethasone had a constructive response where we utilized the structural modification technique in which molecules (icomethasone, betnesol, topicort, flumethasone, paramethasone, triamcinolone, and doxi-betasol) bearing the same pharmacophore as in dexamethasone (ring-A as it is responsible for the binding of the compound to the steroidal receptor), were selected from available drug bank to observe the response of these modified structures against SARs-CoV-2. Desmond Simulation Package was used to run MD simulations for 100 ns following the docking calculations to assess the steady nature and conformational stability of the Dexamethasone-17-acetate-SARs- CoV-2 main protease complexes.

Results: Dexamethasone-17-acetate, the best analog, demonstrated a better pharmacological response than the parent compound and provided information for further designing active inhibitors against inflammatory targets activated by the coronavirus attack. The maximum RMSD value of the Cα-backbone of the SARs-CoV-2 main protease protein is 3.6Å, indicating that the Dexamethasone- 17-acetate-6LU7 protein complex was retained continuously throughout the simulation time.

Conclusion: The present investigation was a search for inhibitors that will help recover patients suffering from COVID and for prophylactic use.

Keywords: COVID-19, SARs-CoV-2, molecular docking, dexamethasone, dexamethasone-17-acetate, Remdesivir.

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[1]
Singh, S.; Florez, H. Coronavirus disease 2019 drug discovery through molecular docking. F1000 Res., 2020, 9, 502.
[http://dx.doi.org/10.12688/f1000research.24218.1] [PMID: 32704354]
[2]
WHO. Weekly epidemiological update on COVID-19 - 1 June 2021. Available from: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-june-2021
[3]
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]
[4]
Ledford, H. Coronavirus breakthrough: Dexamethasone is first drug shown to save lives. Nature, 2020, 582(7813), 469-470.
[http://dx.doi.org/10.1038/d41586-020-01824-5] [PMID: 32546811]
[5]
Horby, P; Landray, M Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19 RECOVERY trial, 2020.
[6]
Khan, S.U. thet Htar, T. Deciphering the binding mechanism of Dexamethasone against SARS-CoV-2 Main Protease: Computational mo-lecular modelling approach. ChemRxiv, 2020, 1-27.
[7]
World Health Organization. Chaib, F. WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients. Available from: https://www. who. int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients (accessed on 16 June 2020)
[8]
Duax, W.L.; Griffin, J.F.; Rohrer, D.C.; Swenson, D.C.; Weeks, C.M. Molecular details of receptor binding and hormonal action of ster-oids derived from X-ray crystallographic investigations. J. Steroid Biochem., 1981, 15, 41-47.
[http://dx.doi.org/10.1016/0022-4731(81)90256-9] [PMID: 7339269]
[9]
Li, F.; Li, W.; Farzan, M.; Harrison, S.C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science, 2005, 309(5742), 1864-1868.
[http://dx.doi.org/10.1126/science.1116480] [PMID: 16166518]
[10]
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]
[11]
Feitosa, E.L.; Júnior, F.T.D.S.S.; Nery Neto, J.A.O.; Matos, L.F.L.; Moura, M.H.S.; Rosales, T.O.; De Freitas, G.B.L. COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main protease inhibitor. Int. J. Med. Sci., 2020, 17(14), 2133-2146.
[http://dx.doi.org/10.7150/ijms.48053] [PMID: 32922174]
[12]
Coperchini, F.; Chiovato, L.; Croce, L.; Magri, F.; Rotondi, M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev., 2020, 53, 25-32.
[http://dx.doi.org/10.1016/j.cytogfr.2020.05.003] [PMID: 32446778]
[13]
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.; Finberg, R.W.; Dierberg, K.; Tapson, V.; Hsieh, L.; Patterson, T.F.; Paredes, R.; Sweeney, D.A.; Short, W.R.; Tou-loumi, G.; Lye, D.C.; Ohmagari, N.; Oh, M.D.; Ruiz-Palacios, G.M.; Benfield, T.; Fätkenheuer, G.; Kortepeter, M.G.; Atmar, R.L.; Creech, C.B.; Lundgren, J.; Babiker, A.G.; Pett, S.; Neaton, J.D.; Burgess, T.H.; Bonnett, T.; Green, M.; Makowski, M.; Osinusi, A.; Nayak, S.; Lane, H.C. ACTT-1 study group members. Remdesivir for the treatment of Covid-19. N. Engl. J. Med., 2020, 383(19), 1813-1826.
[http://dx.doi.org/10.1056/NEJMoa2007764] [PMID: 32445440]
[14]
McCreary, E.K.; Angus, D.C. Efficacy of Remdesivir in COVID-19. JAMA, 2020, 324(11), 1041-1042.
[http://dx.doi.org/10.1001/jama.2020.16337] [PMID: 32821934]
[15]
Business Insider India-Inside the treacherous black market for Remdesivir in India-from private hospitals to distributors Available from:businessinsider.in/science/health/news/how-remdesivir-drug-black-market-working-in-india/articleshow/82210121.cms
[16]
Logo for WebMD. Dexamethasone - Uses, Side Effects, and More Available from: https://www.webmd.com/drugs/2/drug-1027-5021/dexamethasone-oral/dexamethasone-oral/details
[17]
Horby, P.; Lim, W.S.; Emberson, J.R.; Mafham, M.; Bell, J.L.; Linsell, L.; Staplin, N.; Brightling, C.; Ustianowski, A.; Elmahi, E.; Prudon, B.; Green, C.; Felton, T.; Chadwick, D.; Rege, K.; Fegan, C.; Chappell, L.C.; Faust, S.N.; Jaki, T.; Jeffery, K.; Montgomery, A.; Rowan, K.; Juszczak, E.; Baillie, J.K.; Haynes, R.; Landray, M.J. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med., 2021, 384(8), 693-704.
[http://dx.doi.org/10.1056/NEJMoa2021436] [PMID: 32678530]
[18]
Asati, V.; Bajaj, S.; Mahapatra, D.K.; Bharti, S.K. Molecular modeling studies of some thiazolidine-2, 4-dione derivatives as 15-PGDH inhibitors. Med. Chem. Res., 2016, 25(1), 94-108.
[http://dx.doi.org/10.1007/s00044-015-1442-5]
[19]
Chhajed, S.S.; Chaskar, S.; Kshirsagar, S.K.; Haldar, G.M.; Kar Mahapatra, D. Rational design and synthesis of some PPAR-γ agonists: Substituted benzylideneamino-benzylidene-thiazolidine-2,4-diones. Comput. Biol. Chem., 2017, 67, 260-265.
[http://dx.doi.org/10.1016/j.compbiolchem.2017.02.004] [PMID: 28193552]
[20]
Asati, V.; Bharti, S.K.; Rathore, A.; Mahapatra, D.K. SWFB and GA strategies for variable selection in QSAR studies for the validation of thiazolidine-2, 4-dione derivatives as promising antitumor candidates. Indian J. Pharm. Educ. Res., 2017, 51(3), 436-451.
[http://dx.doi.org/10.5530/ijper.51.3.72]
[21]
Pawara, R.; Ahmad, I.; Surana, S.; Patel, H. Computational identification of 2,4-disubstituted amino-pyrimidines as L858R/T790M-EGFR double mutant inhibitors using pharmacophore mapping, molecular docking, binding free energy calculation, DFT study and molecular dynamic simulation. In Silico Pharmacol., 2021, 9(1), 54.
[http://dx.doi.org/10.1007/s40203-021-00113-x] [PMID: 34631361]
[22]
Schrödinger Release (2020-3). Desmond molecular dynamics system, D. E. Shaw Research, Eds. Maestro-Desmond Interoperability Tools, Schrödinger, New York, NY, 2021.
[23]
Patel, H.; Ahmad, I.; Jadhav, H.; Pawara, R.; Lokwani, D.; Surana, S. Investigating the impact of different acrylamide (electrophilic warhead) on osimertinib’s pharmacological spectrum by molecular mechanic and quantum mechanic approach. Comb. Chem. High Throughput Screen., 2022, 25(1), 149-166.
[24]
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]
[25]
Ahmad, I.; Kumar, D.; Patel, H. Computational investigation of phytochemicals from Withaniasomnifera (Indian ginseng/ashwagandha) as plausible inhibitors of GluN2B-containing NMDA receptors. J. Biomol. Struct. Dyn., 2021, 1-13. [ahead of print
[26]
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]
[27]
Martyna, G.J. Remarks on “constant-temperature molecular dynamics with momentum conservation”. Phys. Rev. E Stat. Phys. Plasmas Fluids Relat. Interdiscip. Topics, 1994, 50(4), 3234-3236.
[http://dx.doi.org/10.1103/PhysRevE.50.3234] [PMID: 9962369]
[28]
Zrieq, R.; Ahmad, I.; Snoussi, M.; Noumi, E.; Iriti, M.; Algahtani, F.D.; Patel, H.; Saeed, M.; Tasleem, M.; Sulaiman, S.; Aouadi, K. Kadri, A Tomatidine and patchouli alcohol as inhibitors of SARS-CoV-2 enzymes (3CLpro, PLpro and NSP15) by molecular docking and molecu-lar dynamics simulations. Int. J. Mol. Sci., 2021, 22(19), 10693.
[29]
Lee, H.Y.; Cho, D.Y.; Ahmad, I.; Patel, H.M.; Kim, M.J.; Jung, J.G.; Jeong, E.H.; Haque, M.A.; Cho, K.M. Mining of a novel esterase (est3S) gene from a cow rumen metagenomic library with organosphosphorus insecticides degrading capability: Catalytic insights by site directed mutations, docking, and molecular dynamic simulations. Int. J. Biol. Macromol., 2021, 190, 441-455.
[http://dx.doi.org/10.1016/j.ijbiomac.2021.08.224] [PMID: 34506858]
[30]
Pawara, R.; Ahmad, I.; Nayak, D.; Belamkar, S.; Surana, S.; Kundu, C.N.; Patil, C.; Patel, H. Design and synthesis of the novel, selective WZ4002 analogue as EGFR-L858R/T790M tyrosine kinase inhibitors for targeted drug therapy in non-small-cell lung cancer (NSCLC). J. Mol. Struct., 2021, 1254, 132313.
[31]
AcarÇevik, U; Celik, I; Işık, A; Ahmad, I; Patel, H; Özkay, Y; Kaplancıklı, Z.A. Design, synthesis, molecular modeling, DFT, ADME and biological evaluation studies of some new 1, 3, 4- oxadiazole linked benzimidazoles as anticancer agents and aromatase inhibitors. J. Biomol. Struct. Dyn., 2022, 1-5.
[32]
Ayipo, Y.O.; Ahmad, I.; Najib, Y.S.; Sheu, S.K.; Patel, H.; Mordi, M.N. Molecular modelling and structure-activity relationship of a natu-ral derivative of o-hydroxybenzoate as a potent inhibitor of dual NSP3 and NSP12 of SARS-CoV-2: in silico study. J. Biomol. Struct. Dyn., 2022, 1-19.
[http://dx.doi.org/10.1080/07391102.2022.2026818] [PMID: 35037841]
[33]
Pawara, R.; Ahmad, I.; Nayak, D.; Wagh, S.; Wadkar, A.; Ansari, A.; Belamkar, S.; Surana, S.; Nath, K.C.; Patil, C.; Patel, H. Novel, selec-tive acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-small-cell lung cancer (NSCLC). Bioorg. Chem., 2021, 115, 105234.
[http://dx.doi.org/10.1016/j.bioorg.2021.105234] [PMID: 34399322]
[34]
Ghosh, S.; Das, S.; Ahmad, I.; Patel, H. In silico validation of anti-viral drugs obtained from marine sources as a potential target against SARS-CoV-2 Mpro. J. Indian Chem. Soc., 2021, 98(12), 100272.
[http://dx.doi.org/10.1016/j.jics.2021.100272]
[35]
University of Oxford. Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 Available from: https://www.ox.ac.uk/news/2020-06-16-dexamethasone-reduces-death-hospitalised-patients-severe-respiratory-complications
[36]
Times of India. Coronavirus treatment: Here's why life-saving drug, Dexamethasone is being seen as a better alternative to Remdesivir and Hydroxychloroquine Available from: https://timesofindia.indiatimes.com/life-style/health-fitness/health-news/coronavirus-treatment-heres-why-life-saving-drug-dexamethasone-is-being-seen-as-a-better-alternative-to-remdesivir-and-hydroxychloroquine/photostory/76893355.cms
[37]
Times of India. Coronavirus treatment: Researchers find lifesaving drug Dexamethasone helpful in treating COVID-19; Here is how it works Available from: https://timesofindia.indiatimes.com/life-style/health-fitness/health-news/coronavirus-treatment-by-dexamethasone-researchers-find-lifesaving-drug-dexamethasone-helpful-in-treating-covid-19-here-is-how-it-works/photostory/76419357.cms
[38]
Michelle, R.C. Coronavirus: Dexamethasone proves first life-saving drug., Available from: https://www.bbc.com/news/health-53061281
[39]
Sohini, D. Dexamethasone and remdesivir included in Covid-19 treatment protocol., Available from: https://www.business-standard.com/article/current-affairs/dexamethasone-and-remdesivir-included-in-covid-19-treatment-protocol-120062701419_1.html
[40]
Johnson, R.M.; Vinetz, J.M. Dexamethasone in the management of covid -19. BMJ, 2020, 370, m2648.
[http://dx.doi.org/10.1136/bmj.m2648] [PMID: 32620554]
[41]
Theoharides, T.C.; Conti, P. Dexamethasone for COVID-19? Not so fast. J. Biol. Regul. Homeost. Agents, 2020, 34(3), 1241-1243.
[PMID: 32551464]

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