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Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

Design and In-silico Screening of Peptide Nucleic Acid (PNA) Inspired Novel Pronucleotide Scaffolds Targeting COVID-19

Author(s): Bichismita Sahu*, Santosh Kumar Behera, Rudradip Das, Tanay Dalvi, Arnab Chowdhury, Bhaskar Dewangan, Kiran Kalia and Amit Shard*

Volume 18, Issue 1, 2022

Published on: 23 September, 2020

Page: [26 - 40] Pages: 15

DOI: 10.2174/1573409916666200923143935

Price: $65

Abstract

Introduction: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned into a pandemic, risking many human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive-sense single-stranded enveloped virus and closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced.

Methods: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes non-structural proteins like RNA-dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid-based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are at the advanced stage of clinical trials, including remdesivir. While performing a detailed investigation of the large set of nucleic acid-based drugs, we were surprised to find that the synthetic nucleic acid backbone has been explored very little or rare.

Results: We designed scaffolds derived from peptide nucleic acid (PNA) and subjected them to in- -silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates that compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 12,000mg/kg as opposed to remdesivir (LD50 =1000mg/kg).

Conclusion: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid-derived compound can make it a leading scaffold to design, synthesize and evaluate many similar compounds for the treatment of COVID-19.

Keywords: Covid-19, RNA dependent-RNA polymerase, pronucleotides, peptide nucleic acid, In-silico screening, remdesivir analogues.

Graphical Abstract
[1]
Hillaker, E; Belfer, JJ; Bondici, A; Murad, H; Dumkow, LE Delayed initiation of remdesivir in a COVID-19 positive patient. J. Hum. Pharmacol. Drug. Ther., 2020, 1-15.
[2]
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.
[http://dx.doi.org/10.1126/science.abb7498] [PMID: 32277040]
[3]
Ko, W.C.; Rolain, J.M.; Lee, N.Y.; Chen, P.L.; Huang, C.T.; Lee, P.I.; Hsueh, P.R. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int. J. Antimicrob. Agents, 2020, 55(4)105933
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105933] [PMID: 32147516]
[4]
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]
[5]
Liu, C.; Zhou, Q.; Li, Y.; Garner, L.V.; Watkins, S.P.; Carter, L.J.; Smoot, J.; Gregg, A.C.; Daniels, A.D.; Jervey, S.; Albaiu, D. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci., 2020, 6(3), 315-331.
[http://dx.doi.org/10.1021/acscentsci.0c00272] [PMID: 32226821]
[6]
Morse, J.S.; Lalonde, T.; Xu, S.; Liu, W.R. Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV. ChemBioChem, 2020, 21(5), 730-738.
[http://dx.doi.org/10.1002/cbic.202000047] [PMID: 32022370]
[7]
Zumla, A.; Chan, J.F.W.; Azhar, E.I.; Hui, D.S.C.; Yuen, K.Y. Coronaviruses - drug discovery and therapeutic options. Nat. Rev. Drug Discov., 2016, 15(5), 327-347.
[http://dx.doi.org/10.1038/nrd.2015.37] [PMID: 26868298]
[8]
Jordheim, L.P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat. Rev. Drug Discov., 2013, 12(6), 447-464.
[http://dx.doi.org/10.1038/nrd4010] [PMID: 23722347]
[9]
Belhadi, D; Peiffer-Smadja, N; Yazdanpanah, Y; Mentré, F; Laouénan, C A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19 medRxiv, 2020, 1-14.
[10]
Warren, T.K.; Jordan, R.; Lo, M.K.; Ray, A.S.; Mackman, R.L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H.C.; Larson, N.; Strickley, R.; Wells, J.; Stuthman, K.S.; Van Tongeren, S.A.; Garza, N.L.; Donnelly, G.; Shurtleff, A.C.; Retterer, C.J.; Gharaibeh, D.; Zamani, R.; Kenny, T.; Eaton, B.P.; Grimes, E.; Welch, L.S.; Gomba, L.; Wilhelmsen, C.L.; Nichols, D.K.; Nuss, J.E.; Nagle, E.R.; Kugelman, J.R.; Palacios, G.; Doerffler, E.; Neville, S.; Carra, E.; Clarke, M.O.; Zhang, L.; Lew, W.; Ross, B.; Wang, Q.; Chun, K.; Wolfe, L.; Babusis, D.; Park, Y.; Stray, K.M.; Trancheva, I.; Feng, J.Y.; Barauskas, O.; Xu, Y.; Wong, P.; Braun, M.R.; Flint, M.; McMullan, L.K.; Chen, S.S.; Fearns, R.; Swaminathan, S.; Mayers, D.L.; Spiropoulou, C.F.; Lee, W.A.; Nichol, S.T.; Cihlar, T.; Bavari, S. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature, 2016, 531(7594), 381-385.
[http://dx.doi.org/10.1038/nature17180] [PMID: 26934220]
[11]
Zemlicka, J. Lipophilic phosphoramidates as antiviral pronucleotides. Biochim. Biophys. Acta, 2002, 1587(2-3), 276-286.
[http://dx.doi.org/10.1016/S0925-4439(02)00090-X] [PMID: 12084469]
[12]
Kurreck, J. Antisense technologies. Improvement through novel chemical modifications. Eur. J. Biochem., 2003, 270(8), 1628-1644.
[http://dx.doi.org/10.1046/j.1432-1033.2003.03555.x] [PMID: 12694176]
[13]
Nielsen, P.E.; Egholm, M.; Buchardt, O. Peptide nucleic acid (PNA). A DNA mimic with a peptide backbone. Bioconjug. Chem., 1994, 5(1), 3-7.
[http://dx.doi.org/10.1021/bc00025a001] [PMID: 8199231]
[14]
Kouranov, A.; Xie, L.; de la Cruz, J.; Chen, L.; Westbrook, J.; Bourne, P.E.; Berman, H.M. The RCSB PDB information portal for structural genomics. Nucleic Acids Res., 2006, 34(Database issue), D302-D305.
[http://dx.doi.org/10.1093/nar/gkj120] [PMID: 16381872]
[15]
Systemes, D BIOVIA Discovery Studio Visualizer 2017.Available from: https://discover.3ds.com/discovery-studio-visualizerdownload
[16]
Quevillon, E.; Silventoinen, V.; Pillai, S.; Harte, N.; Mulder, N.; Apweiler, R.; Lopez, R. InterProScan: protein domains identifier. Nucleic Acids Res., 2005, 33(Web Server issue)W116-20
[PMID: 15980438]
[17]
Kerwin, S.M. ChemBioOffice Ultra 2010 suite. J. Am. Chem. Soc., 2010, 132(7), 2466-2467.
[http://dx.doi.org/10.1021/ja1005306] [PMID: 20121088]
[18]
Mirzaei, H.; Beglov, D.; Paschalidis, I.C.; Vajda, S.; Vakili, P.; Kozakov, D. Rigid Body Energy Minimization on Manifolds for Molecular Docking. J. Chem. Theory Comput., 2012, 8(11), 4374-4380.
[http://dx.doi.org/10.1021/ct300272j] [PMID: 23382659]
[19]
Dallakyan, S.; Olson, A.J. Small-Molecule Library Screening by Docking with PyRx.Chemical Biology: Methods and Protocols, Methods in Molecular Biology; Humana Press: New York, NY, 2015, pp. 243-250.
[20]
Tian, W.; Chen, C.; Lei, X.; Zhao, J.; Liang, J. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res., 2018, 46(W1), W363-W367.
[http://dx.doi.org/10.1093/nar/gky473] [PMID: 29860391]
[21]
Heo, L.; Shin, W.H.; Lee, M.S.; Seok, C. GalaxySite: ligand-binding-site prediction by using molecular docking. Nucleic Acids Res., 2014, 42(Web Server issue)W210-4
[http://dx.doi.org/10.1093/nar/gku321] [PMID: 24753427]
[22]
Gao, J.; Zhang, Q.; Liu, M.; Zhu, L.; Wu, D.; Cao, Z.; Zhu, R. bSiteFinder, an improved protein-binding sites prediction server based on structural alignment: more accurate and less time-consuming. J. Cheminform., 2016, 8, 38.
[http://dx.doi.org/10.1186/s13321-016-0149-z] [PMID: 27403208]
[23]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[24]
Daina, A.; Michielin, O.; Zoete, V. iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J. Chem. Inf. Model., 2014, 54(12), 3284-3301.
[http://dx.doi.org/10.1021/ci500467k] [PMID: 25382374]
[25]
Banerjee, P.; Eckert, A.O.; Schrey, A.K.; Preissner, R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res., 2018, 46(W1), W257-W263.
[http://dx.doi.org/10.1093/nar/gky318] [PMID: 29718510]

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