Generic placeholder image

Infectious Disorders - Drug Targets


ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

Research Article

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

Author(s): Trinath Chowdhury, Gourisankar Roymahapatra and Santi M. Mandal*

Volume 21, Issue 4, 2021

Published on: 27 July, 2020

Page: [608 - 618] Pages: 11

DOI: 10.2174/1871526520666200727153643


Background: COVID-19 is a life-threatening novel corona viral infection to our civilization and spreading rapidly. Tremendousefforts have been made by the researchers to search for a drug to control SARS-CoV-2.

Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1.

Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/- mol) was revealed to be the most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-- CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV-2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also performs the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol).

Conclusion: In the host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease, which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast in-vitro to in-vivo analysis towards the development of therapeutics against SARS-CoV-2.

Keywords: COVID-19, novel-corona virus, arsenical drug, darinaparsin, RNA dependent RNA polymerase, proteases.

Graphical Abstract
Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 2020, 367(6485), 1444-1448.
[] [PMID: 32132184]
Clinical trails, Arnea, 2020. Available from:
Dayer, M.R.; Taleb-Gassabi, S.; Saaid Dayer, M. Lopinavir; A potent drug against coronavirus infection: insight from molecular docking study. Arch. Clin. Infect. Dis., 2017, 12(4), e13823.
Liu, J.; Cao, R.; Xu, M.; Wang, X.; Zhang, H.; Hu, H.; Li, Y.; Hu, Z.; Zhong, W.; Wang, M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov., 2020, 6, 16.
[] [PMID: 32194981]
Smith, M.; Smith, J.C. Repurposing therapeutics for COVID-19: supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein-human ACE2 interface. ChemRxiv, 2020.
Lee, H.; Mittal, A.; Patel, K.; Gatuz, J.L.; Truong, L.; Torres, J.; Mulhearn, D.C.; Johnson, M.E. Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings. Bioorg. Med. Chem., 2014, 22(1), 167-177.
[] [PMID: 24332657]
Berry, M.; Fielding, B.C.; Gamieldien, J. Potential broad spectrum inhibitors of the coronavirus 3clpro: a virtual screening and structure-based drug design study. Viruses, 2015, 7(12), 6642-6660.
[] [PMID: 26694449]
Elfiky, A.A.; Mahdy, S.M.; Elshemey, W.M. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J. Med. Virol., 2017, 89(6), 1040-1047.
[] [PMID: 27864902]
Zaher, N.H.; Mostafa, M.I.; Altaher, A.Y. Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors. Acta Pharm., 2020, 70(2), 145-159.
[] [PMID: 31955138]
Hilgenfeld, R. From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J., 2014, 281(18), 4085-4096.
[] [PMID: 25039866]
Zhou, Y.; Hou, Y.; Shen, J.; Huang, Y.; Martin, W.; Cheng, F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov., 2020, 6(1), 14.
[] [PMID: 32194980]
Cui, J.; Li, F.; Shi, Z.L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol., 2019, 17(3), 181-192.
[] [PMID: 30531947]
El-Sayed, S.M.; Ali, M.A.M.; El-Gendy, B.E.M.; Dandash, S.S.; Issac, Y.; Saad, R.; Azab, M.M.; Mohamed, M.R. Identification of novel small molecule inhibitors against the NS3/4A protease of hepatitis C virus genotype 4a. Curr. Pharm. Des., 2018, 24(37), 4484-4491.
[] [PMID: 30501598]
Szollosi, D.; Bill, A. Potential role of endonuclease inhibition and other targets in the treatment of influenza. Curr. Drug Targets, 2020, 21(2), 202-211.
[] [PMID: 31368872]
Giacchello, I.; Musumeci, F.; D’Agostino, I.; Greco, C.; Grossi, G.; Schenone, S. Insights into rna-dependent rna polymerase inhibitors as anti-influenza virus agents. Curr. Med. Chem., 2020, 27, 1-23.
[] [PMID: 31942843]
Mahmud, S.M.N.; Rahman, M.M.; Kar, A.; Jahan, N.; Khan, M.A. Designing of an epitope-based universal peptide vaccine against highly conserved regions in rna dependent rna polymerase protein of human marburg virus: a computational assay. Antiinfect. Agents, 2019, 17, 1-12.
Li, W. A Furin Cleavage Site Inserted into the Spike Protein of SARS-CoV-2: A Structural Implication? Preprints , 2020.
Del Razo, L.M.; Quintanilla-Vega, B.; Brambila-Colombres, E.; Calderón-Aranda, E.S.; Manno, M.; Albores, A. Stress proteins induced by arsenic. Toxicol. Appl. Pharmacol., 2001, 177(2), 132-148.
[] [PMID: 11740912]
Chou, W-C.; Dang, C.V. Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies. Curr. Opin. Hematol., 2005, 12(1), 1-6.
[] [PMID: 15604884]
Hu, J.; Fang, J.; Dong, Y.; Chen, S.J.; Chen, Z. Arsenic in cancer therapy. Anticancer Drugs, 2005, 16(2), 119-127.
[] [PMID: 15655408]
Douer, D.; Tallman, M.S. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J. Clin. Oncol., 2005, 23(10), 2396-2410.
[] [PMID: 15800332]
Kuroki, M.; Ariumi, Y.; Ikeda, M.; Dansako, H.; Wakita, T.; Kato, N. Arsenic trioxide inhibits hepatitis C virus RNA replication through modulation of the glutathione redox system and oxidative stress. J. Virol., 2009, 83(5), 2338-2348.
[] [PMID: 19109388]
Samanta, T.; Roymahapatra, G.; Porto, W.F.; Seth, S.; Ghorai, S.; Saha, S.; Sengupta, J.; Franco, O.L.; Dinda, J.; Mandal, S.M. N, N′-Olefin functionalized bis-imidazolium gold(I) salt is an efficient candidate to control keratitis-associated eye infection. PLoS One, 2013, 8(3), e58346.
[] [PMID: 23554886]
Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford CT, 2013; Gaussian 16, Revision C.01, Gaussian, Inc., Wallingford CT. 2016.
Parr, R.G.; Szentpaly, Lv.; Liu, S. Electrophilicty index. J. Am. Chem. Soc., 1999, 121, 1922-1924.
Roymahapatra, G.; Mandal, S.M.; Porto, W.F.; Samanta, T.; Giri, S.; Dinda, J.; Franco, O.L.; Chattaraj, P.K. Pyrazine functionalized Ag(I) and Au(I)-NHC complexes are potential antibacterial agents. Curr. Med. Chem., 2012, 19(24), 4184-4193.
[] [PMID: 22680631]
Hsu, K-C.; Chen, Y-F.; Lin, S-R.; Yang, J-M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics, 2011, 12(Suppl. 1), S33.
[] [PMID: 21342564]
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., 2010, 31(2), 455-461.
[PMID: 19499576]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[] [PMID: 19399780]
Lill, M.A.; Danielson, M.L. Computer-aided drug design platform using PyMOL. J. Comput. Aided Mol. Des., 2011, 25(1), 13-19.
[] [PMID: 21053052]
Hofmarcher, M.; Mayr, A.; Rumetshofer, E.; Ruch, P.; Renz, P. Large-scale ligand based virtual screening for SARS CoV-2 inhibitors using deep neural networks. Biomolecules arXiv:2004.00979, 2020.
Seo, S.; Park, J.W.; An, D.; Yoon, J.; Paik, H. Supercomputer aided drug repositioning at scale: virtual screening for SARS-CoV-2 protease inhibitor. ChemRxiv, 2020.
Furuta, Y.; Komeno, T.; Nakamura, T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci., 2017, 93(7), 449-463.
[] [PMID: 28769016]
Pharmaceuticals and Medical Devices Agency:Avigan (favipiravir) Review Report
Wu, J.Z.; Larson, G.; Walker, H.; Shim, J.H.; Hong, Z. Phosphorylation of ribavirin and viramidine by adenosine kinase and cytosolic 5′-nucleotidase II: Implications for ribavirin metabolism in erythrocytes. Antimicrob. Agents Chemother., 2005, 49(6), 2164-2171.
[] [PMID: 15917509]
Charan, N.; Lavanya, N.; Praveen, B.; Praveen, A.; Sridevi, A. Antiviral activity of antimony and arsenic oxides. Pharma Chem., 2012, 4(2), 687-689.
Hwang, D-R.; Tsai, Y-C.; Lee, J-C.; Huang, K-K.; Lin, R-K.; Ho, C.H.; Chiou, J.M.; Lin, Y.T.; Hsu, J.T.; Yeh, C.T. Inhibition of hepatitis C virus replication by arsenic trioxide. Antimicrob. Agents Chemother., 2004, 48(8), 2876-2882.
[] [PMID: 15273095]
Gu, Y.; Xu, X. Extended Koopmans’ theorem at the second-order perturbation theory. J. Comput. Chem., 2020, 41(12), 1165-1174.
[] [PMID: 32003902]
Kirchdoerfer, R.N.; Ward, A.B. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat. Commun., 2019, 10(1), 2342.
[] [PMID: 31138817]
Appleby, T.C.; Perry, J.K.; Murakami, E.; Barauskas, O.; Feng, J.; Cho, A.; Fox, D., III; Wetmore, D.R.; McGrath, M.E.; Ray, A.S.; Sofia, M.J.; Swaminathan, S.; Edwards, T.E. Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase. Science, 2015, 347(6223), 771-775.
[] [PMID: 25678663]
Gong, P.; Peersen, O.B. Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase. Proc. Natl. Acad. Sci. USA, 2010, 107(52), 22505-22510.
[] [PMID: 21148772]
Gao, Y.; Yan, L.; Huang, Y.; Liu, F.; Zhao, Y.; Cao, L.; Wang, T.; Sun, Q.; Ming, Z.; Zhang, L.; Ge, J.; Zheng, L.; Zhang, Y.; Wang, H.; Zhu, Y.; Zhu, C.; Hu, T.; Hua, T.; Zhang, B.; Yang, X.; Li, J.; Yang, H.; Liu, Z.; Xu, W.; Guddat, L.W.; Wang, Q.; Lou, Z.; Rao, Z. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 2020, 368(6492), 779-782. [DOI: 10.1126/science.abb7498].
[] [PMID: 32277040]
Snijder, E.J.; Bredenbeek, P.J.; Dobbe, J.C.; Thiel, V.; Ziebuhr, J.; Poon, L.L.; Guan, Y.; Rozanov, M.; Spaan, W.J.; Gorbalenya, A.E. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J. Mol. Biol., 2003, 331(5), 991-1004.
[] [PMID: 12927536]
Sutton, G.; Fry, E.; Carter, L.; Sainsbury, S.; Walter, T.; Nettleship, J.; Berrow, N.; Owens, R.; Gilbert, R.; Davidson, A.; Siddell, S.; Poon, L.L.; Diprose, J.; Alderton, D.; Walsh, M.; Grimes, J.M.; Stuart, D.I. The nsp9 replicase protein of SARS-coronavirus, structure and functional insights. Structure, 2004, 12(2), 341-353.
[] [PMID: 14962394]
Ortiz-Alcantara, J.; Bhardwaj, K.; Palaninathan, S.; Frieman, M.; Baric, R.S.; Kao, C.C. Small molecule inhibitors of the SARS CoV Nsp15 endoribonuclease. Virus Adaptation and Treatment., 2010, 2(1), 125-133.
Walls, A.C.; Park, Y-J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, function and antigenicity of the SARS CoV-2 spike glycoprotein. Cell, 2020, 181(2), 281-292.e6.
[] [PMID: 32155444]
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. 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.
[] [PMID: 32292689]
Elfiky, A.A. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective. J Biomol Struct Dyn, 2020, 39(9), 3204-12.
[PMID: 32338164]
Martin, P.; Jensen, D.M. Ribavirin in the treatment of chronic hepatitis C. J. Gastroenterol. Hepatol., 2008, 23(6), 844-855.
[] [PMID: 18565019]
Mann, K.K.; Wallner, B.; Lossos, I.S.; Miller, W.H., Jr Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin. Investig. Drugs, 2009, 18(11), 1727-1734.
[] [PMID: 19780704]

© 2022 Bentham Science Publishers | Privacy Policy