Are Non-Structural Proteins From SARS-CoV-2 the Target of Hydroxychloroquine? An in Silico Study
-
Ériky Fernandes Guimarães Silva
,
Bruna Fernandes
,
Luan Gabriel Pinto
,
Angélica De Fátima Marcussi
,
Anderson Dillmann Groto
,
Kádima Nayara Teixeira
Abstract
COVID-19 is caused by SARS-CoV-2 which has structural and non-structural proteins (NSP) essential for infection and viral replication. There is a possible binding of SARS-CoV-2 to the beta-1 chain of hemoglobin in red blood cells and thus, decreasing the oxygen transport capacity. Since hydroxychloroquine (HCQ) can accumulate in red cells, there is a chance of interaction of this drug with the virus. To analyze possible interactions between SARS-CoV-2 NSP and hemoglobin with the HCQ using molecular docking and implications for the infected host. This research consisted of a study using bioinformatics tools. The files of the protein structures and HCQ were prepared using the AutoDock Tools software. These files were used to perform molecular docking simulations by AutoDock Vina. The binding affinity report of the generated conformers was analyzed using PyMol software, as well as the chemical bonds formed. The results showed that HCQ is capable of interacting with both SARS-CoV-2 NSP and human hemoglobin. The HCQ/NSP3 conformer, HCQ/NSP5, HCQ/NSP7-NSP8-NSP12, HCQ/NSP9, HCQ/NSP10-NSP16 showed binding affinity. In addition, the interaction between HCQ and hemoglobin resulted in polar bonds. Interaction between SARS-CoV-2 NSP and HCQ indicates that this drug possibly acts by preventing the continuity of infection.
1. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020; 382(8): 727-733.
2. Velavan TP, Meyer CG. The COVID‐19 epidemic. Trop Med Int Heal. 2020; 25(3): 278-280.
3. Malik YA. Properties of Coronavirus and SARS-CoV-2. Malays J Pathol. 2020; 42(1): 3–11.
4. Wu F, Zhao S, Yu B, Chen Y-M, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020; 579(7798): 265-269.
5. Liu Z, Xiao X, Wei X, Li J, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol. 2020; 92(6): 595–601.
6. Wu A, Peng Y, Huang B, Ding X, et al. Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host Microbe. 2020; 27(3): 325-328.
7. Khailany RA, Safdar M, Ozaslan M. Genomic characterization of a novel SARS-CoV-2. Gene Rep. 2020; 19: 100682.
8. Gordon D E, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020; 583(7816): 459-468.
9. Zhou F, Yu T, Du R, Fan G, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229): 1054–1062.
10. He F, Deng Y, Li W. Coronavirus disease 2019: What we know?. J Med Virol. 2020; 92(7): 719-725.
11. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020; 395(10223): 470–473.
12. Thomas-Rüddel D, Winning J, Dickmann P, et al. Coronavirus disease 2019 (COVID-19): update for anesthesiologists and intensivists March 2020. Anaesthesist. 2020; 69(4): 225–235.
13. Wenzhong L, Hualan L. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv.
14. Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020; 10(2): 1271.
15. Zhao X, Liu B, Yu Y, et al. The characteristics and clinical value of chest CT images of novel coronavirus pneumonia. Clin Radiol 2020; 75(5): 335-340.
16. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012; 42(2): 145-153.
17. 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; 7(4): ofaa130.
18. Sinha N, Balayla G. Hydroxychloroquine and covid-19. Postgraduate Medical Journal. 2020; 96(1139).
19. Ferrari V, Cutler DJ. Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane. Biochem Pharmacol. 1991; 41(1): 23-30.
20. Wellems TE. Malaria. How chloroquine works. Nature. 1992; 355(6356): 108-109.
21. Shah B, Modi P, Sagar SR. In silico studies on therapeutic agents for COVID-19: Drug repurposing approach. Life Sci 2020; 252: 117652.
22. LEACH AR. Molecular modeling: principles and applications. 2ª ed. Prentice Hall Pub, 2003: 661.
23. Morris G.M, Lim-Wilby M. (2008) Molecular Docking. In: Kukol A. (eds) Molecular Modeling of Proteins. Methods Molecular Biology™, vol 443. Humana Pres.
24. Trott O, Olson AJ. 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.
25. Shityakov S, Förster C. In silico predictive model to determine vector-mediated transport properties for the blood-brain barrier choline transporter. Adv Appl Bioinform Chem. 2014; 7: 23-36.
26. Angeletti S, Benvenuto D, Bianchi M, et al. COVID‐2019: The role of the nsp2 and nsp3 in its pathogenesis. J Med Virol. 2020; 92(6): 584-588.
27. Claverie J-M. A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19. Viruses. 2020; 12(6): 646.
28. Fehr AR, Channappanavar R, Jankevicius G, et al. The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection. mBio. 2016; 7: e01721-16.
29. Claverie J-M. A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19. Viruses. 2020; 12(6): 646.
30. Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen L-L. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020; 10(4): 313-319.
31. Zhang L, Lin D, Sun X, Curth U, Drosten C, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020; 368(6489): 409-412.
32. Zhu X, Chen J, Tian L, Zhou Y, Xu S, et al. Porcine Deltacoronavirus 1 nsp5 Cleaves DCP1A to Decrease Its Antiviral Ability. J Virol. 2020; 94(15): e02162-19.
33. Zhai Y, Sun F, Li X, Pang H, et al. Insights into SARS-CoV transcription and replication from the structure of the nsp7–nsp8 hexadecamer. Nat Struct Mol Biol. 2005; 12(11): 980–986.
34. Yoshimoto FK. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020; 39(3): 198–216.
35. Subissi L, Imbert I, Ferron F, Collet A, et al. SARS-CoV ORF1b-encoded nonstructural proteins 12–16: Replicative enzymes as antiviral targets. Antiviral Res. 2014; 101: 122-130.
36. Kirchdoerfer RN, Ward AB. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun. 2019; 10(1): 2342.
37. Subissi L, Posthuma CC, Collet A, et al. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc Natl Acad Sci. 2014; 111(37): E3900–E3909.
38. Velthuis AJW, van den Worm SHE, Sims AC, et al. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLoS Pathog. 2010; 6(11): e1001176.
39. Xue J, Moyer A, Peng B, Wu J, et al. Chloroquine Is a Zinc Ionophore. PLoS One. 2014; 9(10):e109180.
40. Deshpande RR, Tiwari AP, Nyayanit N, Modak M. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur J Pharmacol. 2020; 886: 173430.
41. Snijder EJ, Decroly E, Ziebuhr J. The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing. Adv Virus Res. 2016; 96: 59–126.
42. Miknis ZJ, Donaldson EF, Umland TC, et al. Severe Acute Respiratory Syndrome Coronavirus nsp9 Dimerization Is Essential for Efficient Viral Growth. J Virol. 2009; 83(7): 3007–3018.
43. Chen B, Fang S, Tam JP, Liu DX. Formation of stable homodimer via the C-terminal α-helical domain of coronavirus nonstructural protein 9 is critical for its function in viral replication. Virology. 2009; 383(2): 328–337.
44. Egloff M-P, Ferron F, Campanacci V, Longhi S, et al. The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world. Proc Natl Acad Sci USA. 2004; 101(11):3792–3796.
45. Chen Y, Su C, Ke M, Jin X, Xu L, Zhang Z, et al. Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex. PLoS Pathog. 2011; 7(10): e1002294.
46. Encinar JA, Menendez JA. Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA. Viruses. 2020; 12(5): 525.
47. Rosas-Lemus M, Minasov G, Shuvalova L, et al. The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine. bioRxiv Prepr Serv Biol. 2020.
48. Kaushal N, Gupta Y, Goyal M, Khaiboullina SF, et al. Mutational Frequencies of SARS-CoV-2 Genome during the Beginning Months of the Outbreak in USA. Pathogens. 2020; 9(7): 565.
49. Maurya SK, Maurya AK, Mishra N, Siddique HR. Virtual screening, ADME/T, and binding free energy analysis of anti-viral, anti-protease, and anti-infectious compounds against NSP10/NSP16 methyltransferase and main protease of SARS CoV-2. J Recept Signal Transduct Res. 2020; 40(6): 605-612.
50. Yuen C-K, Lam J-Y, Wong W-M, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect. 2020; 9(1): 1418–1428.
51. Quimque MTJ, Notarte KIR, Fernandez RAT, et al. Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms. J Biomol Struct Dyn. 2020; 16: 1–18.
52. da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN. 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.
2. Velavan TP, Meyer CG. The COVID‐19 epidemic. Trop Med Int Heal. 2020; 25(3): 278-280.
3. Malik YA. Properties of Coronavirus and SARS-CoV-2. Malays J Pathol. 2020; 42(1): 3–11.
4. Wu F, Zhao S, Yu B, Chen Y-M, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020; 579(7798): 265-269.
5. Liu Z, Xiao X, Wei X, Li J, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol. 2020; 92(6): 595–601.
6. Wu A, Peng Y, Huang B, Ding X, et al. Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host Microbe. 2020; 27(3): 325-328.
7. Khailany RA, Safdar M, Ozaslan M. Genomic characterization of a novel SARS-CoV-2. Gene Rep. 2020; 19: 100682.
8. Gordon D E, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020; 583(7816): 459-468.
9. Zhou F, Yu T, Du R, Fan G, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229): 1054–1062.
10. He F, Deng Y, Li W. Coronavirus disease 2019: What we know?. J Med Virol. 2020; 92(7): 719-725.
11. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020; 395(10223): 470–473.
12. Thomas-Rüddel D, Winning J, Dickmann P, et al. Coronavirus disease 2019 (COVID-19): update for anesthesiologists and intensivists March 2020. Anaesthesist. 2020; 69(4): 225–235.
13. Wenzhong L, Hualan L. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv.
14. Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020; 10(2): 1271.
15. Zhao X, Liu B, Yu Y, et al. The characteristics and clinical value of chest CT images of novel coronavirus pneumonia. Clin Radiol 2020; 75(5): 335-340.
16. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012; 42(2): 145-153.
17. 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; 7(4): ofaa130.
18. Sinha N, Balayla G. Hydroxychloroquine and covid-19. Postgraduate Medical Journal. 2020; 96(1139).
19. Ferrari V, Cutler DJ. Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane. Biochem Pharmacol. 1991; 41(1): 23-30.
20. Wellems TE. Malaria. How chloroquine works. Nature. 1992; 355(6356): 108-109.
21. Shah B, Modi P, Sagar SR. In silico studies on therapeutic agents for COVID-19: Drug repurposing approach. Life Sci 2020; 252: 117652.
22. LEACH AR. Molecular modeling: principles and applications. 2ª ed. Prentice Hall Pub, 2003: 661.
23. Morris G.M, Lim-Wilby M. (2008) Molecular Docking. In: Kukol A. (eds) Molecular Modeling of Proteins. Methods Molecular Biology™, vol 443. Humana Pres.
24. Trott O, Olson AJ. 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.
25. Shityakov S, Förster C. In silico predictive model to determine vector-mediated transport properties for the blood-brain barrier choline transporter. Adv Appl Bioinform Chem. 2014; 7: 23-36.
26. Angeletti S, Benvenuto D, Bianchi M, et al. COVID‐2019: The role of the nsp2 and nsp3 in its pathogenesis. J Med Virol. 2020; 92(6): 584-588.
27. Claverie J-M. A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19. Viruses. 2020; 12(6): 646.
28. Fehr AR, Channappanavar R, Jankevicius G, et al. The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection. mBio. 2016; 7: e01721-16.
29. Claverie J-M. A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19. Viruses. 2020; 12(6): 646.
30. Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen L-L. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020; 10(4): 313-319.
31. Zhang L, Lin D, Sun X, Curth U, Drosten C, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020; 368(6489): 409-412.
32. Zhu X, Chen J, Tian L, Zhou Y, Xu S, et al. Porcine Deltacoronavirus 1 nsp5 Cleaves DCP1A to Decrease Its Antiviral Ability. J Virol. 2020; 94(15): e02162-19.
33. Zhai Y, Sun F, Li X, Pang H, et al. Insights into SARS-CoV transcription and replication from the structure of the nsp7–nsp8 hexadecamer. Nat Struct Mol Biol. 2005; 12(11): 980–986.
34. Yoshimoto FK. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020; 39(3): 198–216.
35. Subissi L, Imbert I, Ferron F, Collet A, et al. SARS-CoV ORF1b-encoded nonstructural proteins 12–16: Replicative enzymes as antiviral targets. Antiviral Res. 2014; 101: 122-130.
36. Kirchdoerfer RN, Ward AB. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun. 2019; 10(1): 2342.
37. Subissi L, Posthuma CC, Collet A, et al. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc Natl Acad Sci. 2014; 111(37): E3900–E3909.
38. Velthuis AJW, van den Worm SHE, Sims AC, et al. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLoS Pathog. 2010; 6(11): e1001176.
39. Xue J, Moyer A, Peng B, Wu J, et al. Chloroquine Is a Zinc Ionophore. PLoS One. 2014; 9(10):e109180.
40. Deshpande RR, Tiwari AP, Nyayanit N, Modak M. In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2. Eur J Pharmacol. 2020; 886: 173430.
41. Snijder EJ, Decroly E, Ziebuhr J. The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing. Adv Virus Res. 2016; 96: 59–126.
42. Miknis ZJ, Donaldson EF, Umland TC, et al. Severe Acute Respiratory Syndrome Coronavirus nsp9 Dimerization Is Essential for Efficient Viral Growth. J Virol. 2009; 83(7): 3007–3018.
43. Chen B, Fang S, Tam JP, Liu DX. Formation of stable homodimer via the C-terminal α-helical domain of coronavirus nonstructural protein 9 is critical for its function in viral replication. Virology. 2009; 383(2): 328–337.
44. Egloff M-P, Ferron F, Campanacci V, Longhi S, et al. The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world. Proc Natl Acad Sci USA. 2004; 101(11):3792–3796.
45. Chen Y, Su C, Ke M, Jin X, Xu L, Zhang Z, et al. Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex. PLoS Pathog. 2011; 7(10): e1002294.
46. Encinar JA, Menendez JA. Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA. Viruses. 2020; 12(5): 525.
47. Rosas-Lemus M, Minasov G, Shuvalova L, et al. The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine. bioRxiv Prepr Serv Biol. 2020.
48. Kaushal N, Gupta Y, Goyal M, Khaiboullina SF, et al. Mutational Frequencies of SARS-CoV-2 Genome during the Beginning Months of the Outbreak in USA. Pathogens. 2020; 9(7): 565.
49. Maurya SK, Maurya AK, Mishra N, Siddique HR. Virtual screening, ADME/T, and binding free energy analysis of anti-viral, anti-protease, and anti-infectious compounds against NSP10/NSP16 methyltransferase and main protease of SARS CoV-2. J Recept Signal Transduct Res. 2020; 40(6): 605-612.
50. Yuen C-K, Lam J-Y, Wong W-M, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect. 2020; 9(1): 1418–1428.
51. Quimque MTJ, Notarte KIR, Fernandez RAT, et al. Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms. J Biomol Struct Dyn. 2020; 16: 1–18.
52. da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN. 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.
| Files | ||
| Issue | Vol 61 No 2 (2023) | |
| Section | Articles | |
| DOI | https://doi.org/10.18502/acta.v61i2.12533 | |
| Keywords | ||
| Betacoronavirus Coronavirus infections Viral proteins Hydroxychloroquine Computational biology Computer simulation | ||
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How to Cite
1.
Fernandes Guimarães Silva Ériky, Fernandes B, Gabriel Pinto L, Marcussi A, Dillmann Groto A, Nayara Teixeira K. Are Non-Structural Proteins From SARS-CoV-2 the Target of Hydroxychloroquine? An in Silico Study. Acta Med Iran. 2023;61(2):97-104.
