Generic placeholder image

Clinical Cancer Drugs

Editor-in-Chief

ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

Research Article

Hydroxychloroquine (HCQ) Exhibits Better Binding to the Main Protease (Mpro) Compared to Spike Protein (S protein) of SARS-CoV-2: An In-silico Analysis

Author(s): Deepa R. Bandi, SubbaRao V. Tulimilli, Durai Ananda Kumar T., Chandi Kumari Chitturi, Anjalidevi S. Bettadapura, Suma M. Natraj and SubbaRao V. Madhunapantula *

Volume 8, Issue 2, 2021

Published on: 21 December, 2021

Article ID: e101221198736 Pages: 10

DOI: 10.2174/2212697X08666211210103711

Price: $65

conference banner
Abstract

Background: Despite various efforts in preventing and treating SARS-CoV-2 infections; transmission and mortality have been increasing at alarming rates globally. Since its first occurrence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV- -2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns.

Objective: The objective of this study is to identify the ability of HCQ for binding to the most widely studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main protease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ.

Methods: X-ray crystallographic structures of spike glycoprotein and main protease of SARSCoV- 2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using CDocker algorithm, and visualized using Discovery studio visualizer.

Results: Data from molecular docking studies showed very strong binding of HCQ to the main protease compared to spike glycoprotein.

Conclusion: The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.

Keywords: SARS-CoV-2, hydroxychloroquine, spike glycoprotein, protease, vaccine, molecular Docking.

Graphical Abstract
[1]
Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020; 55(3): 105924.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105924] [PMID: 32081636]
[2]
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565-74.
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID: 32007145]
[3]
Macchiagodena M, Pagliai M, Procacci P. Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling. Chem Phys Lett 2020; 750: 137489.
[http://dx.doi.org/10.1016/j.cplett.2020.137489] [PMID: 32313296]
[4]
Rodríguez-Morales AJ, MacGregor K, Kanagarajah S, Patel D, Schlagenhauf P. Going global - Travel and the 2019 novel coronavirus. Travel Med Infect Dis 2020; 33: 101578.
[http://dx.doi.org/10.1016/j.tmaid.2020.101578] [PMID: 32044389]
[5]
Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends 2020; 14(1): 69-71.
[http://dx.doi.org/10.5582/bst.2020.01020] [PMID: 31996494]
[6]
Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 56(1): 105949.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105949] [PMID: 32205204]
[7]
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181(2): 281-292.e6.
[http://dx.doi.org/10.1016/j.cell.2020.02.058] [PMID: 32155444]
[8]
Jin Z, Du X, Xu Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582(7811): 289-93.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481]
[9]
Baildya N, Ghosh NN, Chattopadhyay AP. Inhibitory activity of hydroxychloroquine on COVID-19 main protease: An insight from MD-simulation studies. J Mol Struct 2020; 1219: 128595.
[http://dx.doi.org/10.1016/j.molstruc.2020.128595] [PMID: 32834108]
[10]
Mishra D, Maurya RR, Kumar K, et al. Structurally modified compounds of hydroxychloroquine, remdesivir and tetrahydrocannabinol against main protease of SARS-CoV-2, a possible hope for COVID-19: Docking and molecular dynamics simulation studies. J Mol Liq 2021; 335: 116185.
[http://dx.doi.org/10.1016/j.molliq.2021.116185] [PMID: 33879934]
[11]
King AMQ, Lefkowitz EJ, Mushegian AR, et al. Changes to taxonomy and the international code of virus classification and nomenclature ratified by the international committee on taxonomy of viruses (2018). Arch Virol 2018; 163(9): 2601-31.
[http://dx.doi.org/10.1007/s00705-018-3847-1] [PMID: 29754305]
[12]
Kusanagi K, Kuwahara H, Katoh T, et al. Isolation and serial propagation of porcine epidemic diarrhea virus in cell cultures and partial characterization of the isolate. J Vet Med Sci 1992; 54(2): 313-8.
[http://dx.doi.org/10.1292/jvms.54.313] [PMID: 1318752]
[13]
Li W, Shi Z, Yu M, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science 2005; 310(5748): 676-9.
[http://dx.doi.org/10.1126/science.1118391] [PMID: 16195424]
[14]
Poon LL, Chu DK, Chan KH, et al. Identification of a novel coronavirus in bats. J Virol 2005; 79(4): 2001-9.
[http://dx.doi.org/10.1128/JVI.79.4.2001-2009.2005] [PMID: 15681402]
[15]
Drexler JF, Corman VM, Drosten C. Ecology, evolution and classification of bat coronaviruses in the aftermath of SARS. Antiviral Res 2014; 101: 45-56.
[http://dx.doi.org/10.1016/j.antiviral.2013.10.013] [PMID: 24184128]
[16]
Pedersen NC. An update on feline infectious peritonitis: virology and immunopathogenesis. Vet J 2014; 201(2): 123-32.
[http://dx.doi.org/10.1016/j.tvjl.2014.04.017] [PMID: 24837550]
[17]
Kúdelová M, Belvončíková P, Vrbová M, et al. Detection of murine herpesvirus 68 (MHV-68) in Dermacentor reticulatus Ticks. Microb Ecol 2015; 70(3): 785-94.
[http://dx.doi.org/10.1007/s00248-015-0622-7] [PMID: 25947097]
[18]
Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019; 17(3): 181-92.
[http://dx.doi.org/10.1038/s41579-018-0118-9] [PMID: 30531947]
[19]
Woo PC, Lau SK, Lam CS, et al. Comparative analysis of complete genome sequences of three avian coronaviruses reveals a novel group 3c coronavirus. J Virol 2009; 83(2): 908-17.
[http://dx.doi.org/10.1128/JVI.01977-08] [PMID: 18971277]
[20]
Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol 2012; 86(7): 3995-4008.
[http://dx.doi.org/10.1128/JVI.06540-11] [PMID: 22278237]
[21]
Woo PC, Lau SK, Lam CS, et al. Discovery of a novel bottlenose dolphin coronavirus reveals a distinct species of marine mammal coronavirus in Gammacoronavirus. J Virol 2014; 88(2): 1318-31.
[http://dx.doi.org/10.1128/JVI.02351-13] [PMID: 24227844]
[22]
Ma Y, Zhang Y, Liang X, et al. Origin, evolution, and virulence of porcine deltacoronaviruses in the United States. MBio 2015; 6(2): e00064.
[http://dx.doi.org/10.1128/mBio.00064-15] [PMID: 25759498]
[23]
Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol 2020; 92(4): 418-23.
[http://dx.doi.org/10.1002/jmv.25681] [PMID: 31967327]
[24]
Masters PS. The molecular biology of coronaviruses. Adv Virus Res 2006; 66: 193-292.
[http://dx.doi.org/10.1016/S0065-3527(06)66005-3] [PMID: 16877062]
[25]
Demogines A, Farzan M, Sawyer SL. Evidence for ACE2-utilizing coronaviruses (CoVs) related to severe acute respiratory syndrome CoV in bats. J Virol 2012; 86(11): 6350-3.
[http://dx.doi.org/10.1128/JVI.00311-12] [PMID: 22438550]
[26]
Neuman BW, Kiss G, Kunding AH, et al. A structural analysis of M protein in coronavirus assembly and morphology. J Struct Biol 2011; 174(1): 11-22.
[http://dx.doi.org/10.1016/j.jsb.2010.11.021] [PMID: 21130884]
[27]
DeDiego ML, Alvarez E, Almazán F, et al. A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo. J Virol 2007; 81(4): 1701-13.
[http://dx.doi.org/10.1128/JVI.01467-06] [PMID: 17108030]
[28]
Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 2015; 1282: 1-23.
[http://dx.doi.org/10.1007/978-1-4939-2438-7_1] [PMID: 25720466]
[29]
Cui L, Wang H, Ji Y, et al. The nucleocapsid protein of coronaviruses acts as a viral suppressor of RNA silencing in mammalian cells. J Virol 2015; 89(17): 9029-43.
[http://dx.doi.org/10.1128/JVI.01331-15] [PMID: 26085159]
[30]
van Boheemen S, de Graaf M, Lauber C, et al. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 2012; 3(6): e00473-12.
[http://dx.doi.org/10.1128/mBio.00473-12] [PMID: 23170002]
[31]
Czub M, Weingartl H, Czub S, He R, Cao J. Evaluation of modified vaccinia virus Ankara based recombinant SARS vaccine in ferrets. Vaccine 2005; 23(17-18): 2273-9.
[http://dx.doi.org/10.1016/j.vaccine.2005.01.033] [PMID: 15755610]
[32]
Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 2000; 81(Pt 4): 853-79.
[http://dx.doi.org/10.1099/0022-1317-81-4-853] [PMID: 10725411]
[33]
Alanagreh L, Alzoughool F, Atoum M. The human coronavirus disease COVID-19: its origin, characteristics, and insights into potential drugs and its mechanisms. Pathogens 2020; 9(5): E331.
[http://dx.doi.org/10.3390/pathogens9050331] [PMID: 32365466]
[34]
Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 2005; 309(5742): 1864-8.
[http://dx.doi.org/10.1126/science.1116480] [PMID: 16166518]
[35]
Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3(1): 237-61.
[http://dx.doi.org/10.1146/annurev-virology-110615-042301] [PMID: 27578435]
[36]
Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260-3.
[http://dx.doi.org/10.1126/science.abb2507] [PMID: 32075877]
[37]
Walls AC, Tortorici MA, Snijder J, et al. Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion. Proc Natl Acad Sci USA 2017; 114(42): 11157-62.
[http://dx.doi.org/10.1073/pnas.1708727114] [PMID: 29073020]
[38]
Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog 2018; 14(8): e1007236.
[http://dx.doi.org/10.1371/journal.ppat.1007236] [PMID: 30102747]
[39]
Tang T, Bidon M, Jaimes JA, Whittaker GR, Daniel S. Coronavirus membrane fusion mechanism offers a potential target for antiviral development. Antiviral Res 2020; 178: 104792.
[http://dx.doi.org/10.1016/j.antiviral.2020.104792] [PMID: 32272173]
[40]
Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579(7798): 265-9.
[http://dx.doi.org/10.1038/s41586-020-2008-3] [PMID: 32015508]
[41]
Xia B, Kang X. Activation and maturation of SARS-CoV main protease. Protein Cell 2011; 2(4): 282-90.
[http://dx.doi.org/10.1007/s13238-011-1034-1] [PMID: 21533772]
[42]
Muramatsu T, Kim YT, Nishii W, Terada T, Shirouzu M, Yokoyama S. Autoprocessing mechanism of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CLpro) from its polyproteins. FEBS J 2013; 280(9): 2002-13.
[http://dx.doi.org/10.1111/febs.12222] [PMID: 23452147]
[43]
Du QS, Wang SQ, Zhu Y, et al. Polyprotein cleavage mechanism of SARS CoV Mpro and chemical modification of the octapeptide. Peptides 2004; 25(11): 1857-64.
[http://dx.doi.org/10.1016/j.peptides.2004.06.018] [PMID: 15501516]
[44]
Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020; 368(6489): 409-12.
[http://dx.doi.org/10.1126/science.abb3405] [PMID: 32198291]
[45]
Yang P, Wang X. COVID-19: a new challenge for human beings. Cell Mol Immunol 2020; 17(5): 555-7.
[http://dx.doi.org/10.1038/s41423-020-0407-x] [PMID: 32235915]
[46]
Tang B, He F, Liu D, Fang M, Wu Z, Xu D. AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2. bioRxiv 2020.
[http://dx.doi.org/10.1101/2020.03.03.972133]
[47]
Yang H, Yang M, Ding Y, et al. The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc Natl Acad Sci USA 2003; 100(23): 13190-5.
[http://dx.doi.org/10.1073/pnas.1835675100] [PMID: 14585926]
[48]
Gimeno A, Mestres-Truyol J, Ojeda-Montes MJ, et al. 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(11): E3793.
[http://dx.doi.org/10.3390/ijms21113793] [PMID: 32471205]
[49]
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform 2011; 3: 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[50]
Berman HM, Westbrook J, Feng Z, et al. The protein data bank. Nucleic Acids Res 2000; 28(1): 235-42.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[51]
Biovia DS. Discovery studio modeling environment. Release 2017.
[52]
Lin CW, Tsai CH, Tsai FJ, et al. Characterization of trans- and cis-cleavage activity of the SARS coronavirus 3CLpro protease: basis for the in vitro screening of anti-SARS drugs. FEBS Lett 2004; 574(1-3): 131-7.
[http://dx.doi.org/10.1016/j.febslet.2004.08.017] [PMID: 15358553]
[53]
Chhetri A, Chettri S, Rai P, Mishra DK, Sinha B, Brahman D. Synthesis, characterization and computational study on potential inhibitory action of novel azo imidazole derivatives against COVID-19 main protease (Mpro: 6LU7). J Mol Struct 2021; 1225: 129230.
[http://dx.doi.org/10.1016/j.molstruc.2020.129230] [PMID: 32963413]
[54]
Keretsu S, Bhujbal SP, Cho SJ. Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. Sci Rep 2020; 10(1): 17716.
[http://dx.doi.org/10.1038/s41598-020-74468-0] [PMID: 33077821]
[55]
Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009; 53(8): 3416-21.
[http://dx.doi.org/10.1128/AAC.01509-08] [PMID: 19506054]
[56]
Pastick KA, Okafor EC, Wang F, et al. Review: hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis 2020 2020; 7(4): ofaa130.
[http://dx.doi.org/10.1093/ofid/ofaa130] [PMID: 32363212]
[57]
Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect 2017; 5(1): e00293.
[http://dx.doi.org/10.1002/prp2.293] [PMID: 28596841]
[58]
Quiros Roldan E, Biasiotto G, Magro P, Zanella I. The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Pharmacol Res 2020; 158: 104904.
[http://dx.doi.org/10.1016/j.phrs.2020.104904] [PMID: 32430286]
[59]
Nimgampalle M, Devanathan V, Saxena A. Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets. J Biomol Struct Dyn 2020; 39(14): 4949-61.
[http://dx.doi.org/10.1080/07391102.2020.1782265] [PMID: 32579059]
[60]
Celi KI, Onay-Besi Kci A, Ayhan-Kilcigi LG. Approach to the mechanism of action of hydroxychloroquine on SARS-CoV-2: a molecular docking study. J Biomol Struct Dyn 2021; 39(15): 5792-8.
[http://dx.doi.org/10.1080/07391102.2020.1792993] [PMID: 32677545]
[61]
Narkhede R, CR, Ambhore J, Shinde S. The molecular docking study of potential drug candidates showing anti-covid-19 activity by exploring of therapeutic targets of SARS-CoV-2. Eurasian J Med Oncol 2020; 4(3): 185-95.
[62]
Badraoui R, Adnan M, Bardakci F, Alreshidi MM. Chloroquine and hydroxychloroquine interact differently with ACE2 domains reported to bind with the coronavirus spike protein: mediation by ACE2 polymorphism. Molecules 2021; 26(3): 673.
[http://dx.doi.org/10.3390/molecules26030673] [PMID: 33525415]
[63]
Li Z, Li X, Huang YY, et al. Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs. Proc Natl Acad Sci USA 2020; 117(44): 27381-7.
[http://dx.doi.org/10.1073/pnas.2010470117] [PMID: 33051297]
[64]
Braz HLB, Silveira JAM, Marinho AD, et al. In silico study of azithromycin, chloroquine and hydroxychloroquine and their potential mechanisms of action against SARS-CoV-2 infection. Int J Antimicrob Agents 2020; 56(3): 106119.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.106119] [PMID: 32738306]
[65]
Jitender Kumar Malik, H S, Sarvesh Sharma, Satish Sarankar. Hydroxychloroquine as potent inhibitor of covid -19 main protease: grid based docking approach. Eurasian J Med Oncol 2020; 4(3): 219-26.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy