In Silico Study of Curcumin and Folic Acid as Potent Inhibitors of Human Transmembrane Protease Serine 2 in the Treatment of COVID-19

© 2020 by the Authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )

Download PDF

Cite

XML

Abstract

Background. Human transmembrane protease 2 (TMPRSS2) protein is essential for priming spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with human angiotensin-converting enzyme 2 (ACE2) surface receptor to facilitate viral invasion into host human cell through ACE2 receptor. Impeding TMPRSS2 protein activity is currently a preferred choice of the treatment of coronavirus disease 2019 (COVID-19) which is caused by SARS-CoV-2. Curcumin and folic acid are potential candidates for inhibiting TMPRSS2.

Objective. The present study aimed to demonstrate the inhibitory activities of curcumin and folic acid, along with known human serine protease inhibitors such as nafamostat and camostat, on TMPRSS2.

Methods. Curcumin and folic acid, along with nafamostat and camostat, were docked on a modeled human TMPRSS2 protein 3D structure. Nafamostat and curcumin interactions with targeted TMPRSS2 protein were identical whereas camostat and folic acid displayed similar interactions.

Results. The hydrogen bond (H-bond) energies of docked curcumin, folic acid, nafamostat, and camostat were ?19.86 kJ/mol, ?17.63 kJ/mol, ?10.53 kJ/mol, and ?14.41 kJ/mol, respectively. Higher H-bond energies could strengthen protein-ligand interactions. Our results showed binding site similarities between curcumin and nafamostat as well as folic acid and camostat.

Conclusion. The current in silico simulation suggested that curcumin and folic acid displayed binding poses with TMPRSS2 which are similar to nafamostat and camostat. Therefore, curcumin and folic acid could emerge as potential drug candidates to control COVID-19.

Keywords

Human transmembrane protease 2

ngiotensin-converting enzyme 2

ike protein

evere acute respiratory syndrome coronavirus 2

Curcumin

Folic acid

Conflict of interest

The authors declare that they have no conflicts of interest of any kind for this study.

References

[1]

Nicola, M.; Alsafi, Z.; Sohrabi, C.; Kerwan, A.; Al-Jabir, A.; Iosifidis, C.; Agha, M.; Agha, R. The Socio-economic Implications of the Coronavirus Pandemic (COVID-19): A Review. Int. J. Surg., 2020, 78, 185–193.

[2]

Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Kruger, N.; Herrler, T.; Erichsen, S.; Scheirgens, T.S.; Herrler, G.; Wu, N.; Nitsche, A.; Muller, M.A.; Drosten, C.; Pohlmann, S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and is Blocked by Clinically Proven Protease Inhibitor. Cell, 2020, 181(2), 271–280.

[3]

Li, X.; Ma, X. Acute Respiratory Failure in COVID-19: Is it “Typical” ARDS Critical. Care, 2020, 24, 198.

[4]

Bosch, B.J.; van der Zee, R.; de Haan, C.A.; Rottier, P.J. The Corovavirus Spike Protein is a Class I Virus Fusion Protein: Structural and Functional Characterization of the Fusion Core Complex. J. Virol., 2003, 77(16), 8801–8811.

[5]

Gierer, S.; Bertram, S.; Kaup, F.; Wrensch, F.; Heurich, A.; Kramer-Kuhl, A.; Welsch, K.; Winkler, M.; Meyer, B.; Drosten, C.; Dittmer, U.; von Hahn, T.; Simmons, G.; Hofmann, H.; Pohlmann, S. The Spike Protein of the Emerging BetacoronavirusEMC Uses a Novel Coronavirus Receptor for Entry, can be Activated by TMPRSS2, and is Targeted by Neutralizing Antibodies. J. Virol., 2013, 87(10), 5502–5511.

[6]

Harbig, A.; Mernberger, M.; Bittel, L.; Pleschka, S.; Schughart, K.; Steinmetzer, T.; Stiewe, T.; Nist, A.; Bottcher-Friebertshauser, E. Transcriptome Profiling and Protease Inhibition Experiments Identify Proteases that Activate H3N2 Influenza A and Influenza B Viruses in Murine Airway. J. Biol. Chem., 2020, 295(33), 11388–11407.

[7]

Shirato, K.; Kawase, M.; Matsuyama, S. Middle East Respiratory Syndrome Coronavirus Infection Mediated by the Transmembrane Serine Protease TMPRSS2. J. Virol., 2013, 87(23), 12552–12561.

[8]

Hatesuer, B.; Bertram, S.; Mehnert, M.; Bahgat, M.M.; Nelson, P.S.; Pohlmann, S.; Schughart, K. Tmprss2 is Essential for Influenza H1N1 Virus Pathogenesis in Mice. PLoS Pathog., 2013, 9, e1003774.

[9]

Sakai, K.; Ami, Y.; Tahara, M.; Kubota, T.; Anraku, M.; Abe, M.; Nakajima, N.; Sekizuka, T.; Shirato, K.; Suzaki, Y.; Ainai, A.; Nakatsu, Y.; Kanou, K.; Nakamura, K.; Suzuki, T.; Komase, K.; Nobusawa, E.; Maenaka, K.; Kuroda, M.; Hasegawa, H.; Kawaoka, Y.; Tashiro, M.; Takeda, M. The Host Protease TMPRSS2 Plays a Major Role in In Vivo Replication of Emerging H7N9 and Seasonal Influenza Viruses. J. Virol., 2014, 88(10), 5608–5616.

[10]

Hondermarck, H.; Barlett, N.W.; Nurcombe, V. The Role of Growth Factor Receptors in Viral Infections: An Opportunity for Drug Repurposing against Emerging Viral Diseases such as COVID-19? FASEB Bioadv., 2020, 2, 296–303.

[11]

The Impact of Camostat Mesilate on COVID-19 Infection (CAMOCO-19). Clinical Trails. NIH U.S. National Library of Medicine, 2020, NCT04321096, Available from: https://clinicaltrials.gov/ct2/show/NCT04321096. [Last accessed on 2020 Oct 14].

[12]

Kawase, M.; Shirato, K.; Van der Hoek, L.; Taguchi, F.; Matsuyama, S. Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome Coronavirus Entry. J. Virol., 2012, 18(12), 6537–6545.

[13]

Hoffmann, M.; Schroeder, S.; Kleine-Weber, H.; Muller, M.A.; Drosten, C.; Pohlmann, S. Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19. Antimictob. Agents Chemother., 2020, 64(6), e00754–20.

[14]

Mathew, D.; Hsu, W. Antiviral Potential of Curcumin. J. Funct. Foods, 2018, 40(1), 692–699.

[15]

Manoharan, Y.; Haridas, V.; Vasanthakmar, K.C.; Muthu, S.; Thavoorullah, F.F.; Shetty, P. Curcumin: A Wonder Drug as Preventive Measure for COVID19 Management. Ind. J. Clin. Biochem., 2020, 35(3), 373–375.

[16]

Das, S.; Sarmah, S.; Lyndem, S.; Roy, A.S. An Investigation into the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking Study. J. Biol. Struct. Dyn., 2020, 13, 1–11.

[17]

Sheybani, Z.; Dokoohaki, M.H.; Nagahdaripour, M.; Dehdashti,M.; Zolghadr, H.; Moghadami, M.; Mansoompour, S.M.; Zolghadr, A.M. The Role of Folic Acid in the Management of Respiratory Disease Caused by COVID-19. ChemRxiv, 2020.

[18]

Li, H.; Wu, C.; Yang, Y.; Liu, Y.; Zhang, P.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Zheng, M.; Chen, L. Furin, a Potential Therapeutic Target for COVID-19. ChinaXiv, 2020.

[19]

Chothia, C.; Lesk, A.M. The Relation between the Divergence of Sequence and Structure in Proteins. EMBO J., 1986, 5(4), 823–826.

[20]

Kaczanowski, S.; Zielenkiewicz, P. Why Similar Protein Sequences Encode Similar Three-dimentional Structures? Theor. Chem. Acc., 2010, 125(3-6), 643–650.

[21]

Bordoli, L.; Kiefer, F.; Arnold, K.; Benkert, P.; Battey, J.; Schwede, T. Protein Structure Homology Modeling Using SWISS-MODEL Workspace. Nat. Protoc., 2008, 4, 1–13.

[22]

Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G. Schmidt, T.; Kiefer, F. SWISS-MODEL: Modeling Protein Tertiary and Quaternary Structure Using Evolutionary Information. Nucleic Acids Res., 2014, 42(W1), 252–258.

[23]

Read, R.J.; Adams, P.D.; Arendall, W.B. 3rd.; Brunger, A.T.; Emsley, P.; Joosten, R.P.; Kleywegt, G.J.; Krissinel, E.B.; Lutteke, T.; Otwinowski, Z.; Perrakis, A.; Richardson, J.S.; Sheffler, W.H.; Smith, J.L.; Tickle, I.J.; Vriend, G.; Zwart, P.H. A New Generation of Crystallographic Validation Tools for the Protein Data Bank. Structure, 2011, 19(10), 1395–1412.

[24]

Savarino, A. In Silico Docking of HIV-1 Integrase Inhibitors Reveals a Novel Drug Type Acting on an Protein/DNA Reaction Intermediate. Retrovirology, 2007, 4(21), 1–15.

[25]

Dubey, K.; Dubey, R.; Gupta, R.G.A. In-Silico Reverse Docking Studies for the Identification of Potential of Betanin on Some Proteins Involved in Diabetes and its Complications. J. Drug Deliv. Ther., 2019, 9, 72–74.

[26]

Madhuri, M.; Rao, P.C.; Avupati, V. In Silico Protein-ligand Docking Studies on Thiazolidinediones as Potential Anticancer Agents. Int. J. Comput. Appl., 2014, 95, 13–16.

[27]

Heble, N.K.; Mavillapalli, R.C.; Selvaraj, R.; Jeyabalan, S. Molecular Docking Studies of Phytoconstituents Identified I Crocus sativus, Curcuma longa, Cassia occidentalis and Moringa oleifera on Thymidylate Synthase an Protein Target for AntiCancer Activity. J.Appl. Pharm. Sci., 2016, 6, 131–135.

[28]

Mavillapalli, R.C.; Jayabalan, S.; Muthusamy, S. Molecular Docking Studies of Phytoconstituents Identified in Cinnamomum verum and Coriandrum sativum on HMG COA Reductase a Protein Target for Antihyperlipidemic Activity. Int. J. Pharm. Sci. Res., 2017, 8, 4172–4179.

[29]

Elmezayen, A.D.; Al-Obaidi, A.; Sabin, A.T.; Yelekci, K. Drug Repurposing of Coronavirus (OVID-19): In Silico Screening of Known Drugs against 3CL Hydrolase and Protease Proteins. J. Biomol. Struct. Dyn., 2020, 26, 1–13.

[30]

Chen, D.; Oezguen, N.; Urvil, P.; Ferguson, C.; Dann, S.M.; Savidge, T.C. Regulation of Protein-ligand Binding Affinity by Hrogen Bond Pairing. Sci. Adv. 2016, 2, e1501240.

[31]

Donaldson, S.H.; Hirsh, A.; Li, D.C.; Holloway, G.; Chao, J.; Boucher, R.C.; Gabriel, S.E. Regulation of the Epithelial Sodium Channel by Serine Proteases in Human Airways. J. Biol. Chem., 2002, 277, 8338–8345.

[32]

Kim, T.S.; Heinlein, C.; Hackman, R.C.; Nelson, P.S. Phenotypic Analysis of Mice Lacking the Tmprss2-encoded Protease. Mol. Cell Biol., 2006, 26, 965–975.

[33]

National Library of Medicine. The Impact of Camostat Mesilate on COVID-19 Infection (CamoCO-19). Clinical Trails. NIH U.S. National Library of Medicine. NCT04321096. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04321096.

[34]

Uno, Y. Camostat Mesilate Therapy for COVID-19. Emerg. Med. Int., 2020, 29, 1–2.

[35]

Braun, E.; Saulter, D. Furin-mediated Protein Processing in Infectious Diseases and Cancer. Clin. Transl. Immunol., 2019, 8(8), e1073.

Previous article in this issue

Next article in this issue

INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823, Published by AccScience Publishing