Computational Insights into the Drug Repurposing and Synergism of FDA-approved Influenza Drugs Binding with SARS-CoV-2 Protease against COVID-19

Shazia Parveen^1, , Rua B. Alnoman¹, Abrar A. Bayazeed² and Alaa M. Alqahtani³

¹Faculty of Science, Chemistry Department, Taibah University, Yanbu Branch, 46423, Yanbu, Saudi Arabia

²Chemistry Department, Faculty of Applied Science, Umm Al-Qura University, 21955, Makkah, Saudi Arabia

³Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia

Cite this paper:
Shazia Parveen, Rua B. Alnoman, Abrar A. Bayazeed and Alaa M. Alqahtani. Computational Insights into the Drug Repurposing and Synergism of FDA-approved Influenza Drugs Binding with SARS-CoV-2 Protease against COVID-19. American Journal of Microbiological Research. 2020; 8(3):93-102. doi: 10.12691/ajmr-8-3-3

Abstract

The concept of drug repurposing is extensively used currently to identify already approved/under investigation/discarded potential drugs for various other diseases, owing to the fact that many drugs could have multiple protein targets and many diseases share overlapping molecular pathways. The geographical spread of COVID-19 infections originating from Wuhan, China, has provided an opportunity to study the natural history of the recently emerged virus. The source of the SARS-CoV-2 is yet not known, even though the initial cases have been connected with the Huanan South China Seafood Market. In this study, the bioactivity of FDA-approved influenza drugs (Baloxavir, Oseltamivir, Peramivir and Zanamivir) were evaluated as inhibitors for COVID-19 using computational modeling approaches. The nominated drugs were docked on SARS-CoV-2 main protease (PDB ID: 6LU7) and also with SARS HCoV (PDB ID: 6NUR) for comparison, to evaluate the binding affinity of these drugs. ADMET and DFT analyses were also further carried out to analyze the potential of these influenza drugs as an effective inhibitor against COVID-19. The DFT calculations were performed to estimate the thermal parameters, dipole moment of the investigated drugs; additionally, chemical reactivity descriptors were investigated. The results of molecular docking with respect to binding energies in Kcal/mol suggested that binding affinity of influenza drugs with SARS-CoV-2 was in the order Zanamivir > Baloxavir > Oseltamivir > Peramivir. The findings of this study can facilitate rational drug design targeting the SARS-Cov-2 main protease.

Keywords:
COVID-19 influenza drugs 3CL^pro molecular docking DFT

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727-733.
[2]	Benvenuto, D.; Giovanetti, M.; Salemi, M.; Prosperi, M.; De Flora, C.; Junior Alcantara, L.C.; Angeletti, S.; Ciccozzi, M. The global spread of 2019-nCoV: a molecular evolutionary analysis. Pathog. Glob. Health 2020, 114, 64-67.
[3]	Ibrahim, I.M.; Abdelmalek, D.H.; Elshahat, M.E.; Elfiky, A.A. COVID-19 spike-host cell receptor GRP78 binding site prediction. J. Infect. 2020, 80, 554-562.
[4]	Belouzard, S.; Millet, J.K.; Licitra, B.N.; Whittaker, G.R. Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein. Viruses 2012, 4, 1011-1033.
[5]	Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270-273.
[6]	Perlman, S. Another Decade, Another Coronavirus. N. Engl. J. Med. 2020, 382, 760-762.
[7]	Parvathaneni, V.; Kulkarni, N.S.; Muth, A.; Gupta, V. Drug repurposing: a promising tool to accelerate the drug discovery process. Drug Discov. Today 2019, 24, 2076-2085.
[8]	Naylor, S.; Kauppi, D.M.; Schonfeld, J.M. Therapeutic drug repurposing, repositioning and rescue: Part II: Business review. Drug Discov. World 2015, 16, 57-72.
[9]	Rothan, H.A.; Byrareddy, S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J. Autoimmun. 2020, 109, 102433.
[10]	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.; et al. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6, 315-331.
[11]	Linton, N.M.; Kobayashi, T.; Yang, Y.; Hayashi, K.; Akhmetzhanov, A.R.; Jung, S.; Yuan, B.; Kinoshita, R.; Nishiura, H. Incubation Period and Other Epidemiological Characteristics of 2019 Novel Coronavirus Infections with Right Truncation: A Statistical Analysis of Publicly Available Case Data. J. Clin. Med. 2020, 9, 538.
[12]	Abraham, G.M.; Morton, J.B.; Saravolatz, L.D. Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza. Clin. Infect. Dis. 2020.
[13]	McClellan, K.; Perry, C.M. Oseltamivir. Drugs 2001, 61, 263-283.
[14]	Birnkrant, D.; Cox, E. The Emergency Use Authorization of Peramivir for Treatment of 2009 H1N1 Influenza. N. Engl. J. Med. 2009, 361, 2204-2207.
[15]	Hayden, F.G.; Gubareva, L. V.; Monto, A.S.; Klein, T.C.; Elliott, M.J.; Hammond, J.M.; Sharp, S.J.; Ossi, M.J. Inhaled Zanamivir for the Prevention of Influenza in Families. N. Engl. J. Med. 2000, 343, 1282-1289.
[16]	Sepay, N.; Sepay, N.; Al Hoque, A.; Mondal, R.; Halder, U.C.; Muddassir, M. In silico fight against novel coronavirus by finding chromone derivatives as inhibitor of coronavirus main proteases enzyme. Struct. Chem. 2020.
[17]	Iftikhar, H.; Ali, H.N.; Farooq, S.; Naveed, H.; Shahzad-ul-Hussan, S. Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach. Comput. Biol. Med. 2020, 122, 103848.
[18]	Hagar, M.; Ahmed, H.A.; Aljohani, G.; Alhaddad, O.A. Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations. Int. J. Mol. Sci. 2020, 21, 3922.
[19]	Robson, B. Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus. Comput. Biol. Med. 2020, 119, 103670.
[20]	Robson, B. COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance. Comput. Biol. Med. 2020, 121, 103749.
[21]	Gimeno, A.; Mestres-Truyol, J.; Ojeda-Montes, M.J.; Macip, G.; Saldivar-Espinoza, B.; Cereto-Massagué, A.; Pujadas, G.; Garcia-Vallvé, S. Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition. Int. J. Mol. Sci. 2020, 21, 3793.
[22]	da Silva, J.K.R.; Figueiredo, P.L.B.; Byler, K.G.; Setzer, W.N. Essential Oils as Antiviral Agents, Potential of Essential Oils to Treat SARS-CoV-2 Infection: An In-Silico Investigation. Int. J. Mol. Sci. 2020, 21, 3426.
[23]	Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019, 47, W357-W364.
[24]	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. 2009.
[25]	Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020, 582, 289-293.
[26]	Kirchdoerfer, R.N.; Ward, A.B. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat. Commun. 2019, 10, 2342.
[27]	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, 2785-2791.
[28]	Schmidt, M.W.; Baldridge, K.K.; Boatz, J.A.; Elbert, S.T.; Gordon, M.S.; Jensen, J.H.; Koseki, S.; Matsunaga, N.; Nguyen, K.A.; Su, S.; et al. General atomic and molecular electronic structure system. J. Comput. Chem. 1993, 14, 1347-1363.
[29]	Gordon, M.S.; Schmidt, M.W. Advances in electronic structure theory. In Theory and Applications of Computational Chemistry; Elsevier, 2005; pp. 1167-1189.
[30]	Shahab, S.; Sheikhi, M.; Filippovich, L.; Anatol’evich, D.E.; Yahyaei, H. Quantum chemical modeling of new derivatives of ( E,E )-azomethines: Synthesis, spectroscopic (FT-IR, UV/Vis, polarization) and thermophysical investigations. J. Mol. Struct. 2017, 1137, 335-348.
[31]	Shahab, S.; Filippovich, L.; Sheikhi, M.; Kumar, R.; Dikusar, E.; Yahyaei, H.; Muravsky, A. Polarization, excited states, trans-cis properties and anisotropy of thermal and electrical conductivity of the 4-(phenyldiazenyl)aniline in PVA matrix. J. Mol. Struct. 2017, 1141, 703-709.
[32]	Shahab, S. Spectroscopic (Polarization, ExcitedState, FT-IR, UV/Vis and 1H NMR) and Thermophysical Investigations of New Synthesized Azo Dye and Its Application in Polarizing Film. Am. J. Mater. Synth. Process. 2017, 2, 17.
[33]	Cheng, W.; Yuan, Y.; Qiu, N.; Peng, P.; Sheng, R.; Hu, Y. Identification of novel 4-anilinoquinazoline derivatives as potent EGFR inhibitors both under normoxia and hypoxia. Bioorganic Med. Chem. 2014, 22, 6796-6805.
[34]	Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23, 3-25.
[35]	Abdel-Mohsen, H.T.; Abood, A.; Flanagan, K.J.; Meindl, A.; Senge, M.O.; El Diwani, H.I. Synthesis, crystal structure, and ADME prediction studies of novel imidazopyrimidines as antibacterial and cytotoxic agents. Arch. Pharm. (Weinheim). 2020, 353.
[36]	Bzówka, M.; Mitusińska, K.; Raczyńska, A.; Samol, A.; Tuszyński, J.A.; Góra, A. Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design. Int. J. Mol. Sci. 2020, 21, 3099.
[37]	Kojetin, D.J.; Burris, T.P. Small Molecule Modulation of Nuclear Receptor Conformational Dynamics: Implications for Function and Drug Discovery. Mol. Pharmacol. 2013, 83, 1-8.
[38]	Schena, A.; Griss, R.; Johnsson, K. Modulating protein activity using tethered ligands with mutually exclusive binding sites. Nat. Commun. 2015, 6, 7830.
[39]	Papaneophytou, C.P.; Grigoroudis, A.I.; McInnes, C.; Kontopidis, G. Quantification of the Effects of Ionic Strength, Viscosity, and Hydrophobicity on Protein-Ligand Binding Affinity. ACS Med. Chem. Lett. 2014, 5, 931-936.
[40]	Zhao, X.; Xu, Z.; Li, H. NSAIDs Use and Reduced Metastasis in Cancer Patients: results from a meta-analysis. Sci. Rep. 2017, 7, 1875.
[41]	Chelliah, V.; Blundell, T.L.; Fernández-Recio, J. Efficient Restraints for Protein-Protein Docking by Comparison of Observed Amino Acid Substitution Patterns with those Predicted from Local Environment. J. Mol. Biol. 2006, 357, 1669-1682.
[42]	Zheng, Y.; Zheng, M.; Ling, X.; Liu, Y.; Xue, Y.; An, L.; Gu, N.; Jin, M. Design, synthesis, quantum chemical studies and biological activity evaluation of pyrazole-benzimidazole derivatives as potent Aurora A/B kinase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 3523-3530.
[43]	Middleton, E.; Kandaswami, C.; Theoharides, T.C. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 2000, 52, 673-751.
[44]	Xavier, S.; Periandy, S.; Ramalingam, S. NBO, conformational, NLO, HOMO-LUMO, NMR and electronic spectral study on 1-phenyl-1-propanol by quantum computational methods. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2015, 137, 306-320.