Abstract

Objective:

This study aimed to investigate the inhibitory effects of sedative, analgesic and anaesthetic drugs on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human angiotensin converting enzyme-2 (ACE-2) and SARS-CoV-2-ACE-2 complex through molecular docking and their potential use for the treatment of coronavirus disease-2019 (COVID-19).

Materials and Methods:

In this study, molecular docking was employed to investigate the molecular interaction between drugs under clinical tests (chloroquine, hydroxychloroquine and nelfinavir) and the most commonly used drugs for sedation, analgesia and anaesthesia, such as inhibitors (desflurane, dexmedetomidine, fentanyl, ketamine, midazolam, propofol, remifentanil and sevoflurane) of three different enzymes (6LU7, 1R4L and 6LZG). Autodock 4.2 Lamarckian Genetic Algorithm was used to analyse the probability of the molecular docking. The evaluation was based on docking points calculated by Biovia Discovery Studio Visualizer 2020. As a result of the molecular docking, interaction types, such as hydrogen-electrostatic and van der Waals between enzymes and drugs, were determined and the results were compared.

Results:

Among the drugs included in the study, fentanyl had a low binding energy (-8.75 to -7.64 kcal/mol) for SARS-CoV-2, ACE-2 and SARS-CoV-2-ACE-2 complex and can inhibit these proteins at low concentrations. Apart from fentanyl, midazolam, ketamine, propofol and remifentanil can also inhibit proteins; however, sevoflurane and desflurane were found to be ineffective.

Conclusion:

Our findings suggest that fentanyl is preferable for sedation, analgesia and anaesthesia in COVID-19 patients and that total intravenous anaesthesia can be preferred for general anaesthesia. However, experimental and clinical studies are required to determine the efficacy of these substances in treatment.

Keywords: Anaesthesia, COVID-19, sedation, molecular docking

References

  1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-13.
  2. Sohrabi C, Alsafi Z, O’Neill N, Khan M, Kerwan A, Al-Jabir A, et al. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg 2020;76:71-6.
  3. Greenland JR, Michelow MD, Wang L, London MJ. COVID-19 Infection: Implications for Perioperative and Critical Care Physicians. Anesthesiology 2020;132:1346-61.
  4. Ammar MA, Sacha GL, Welch SC, Bass SN, Kane-Gill SL, Duggal A, et al. Sedation, Analgesia, and Paralysis in COVID-19 Patients in the Setting of Drug Shortages. J Intensive Care Med 2021;36:157-74.
  5. Gommers D, Bakker J. Medications for analgesia and sedation in the intensive care unit: an overview. Crit Care 2008;12 Suppl 3:S4.
  6. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263-306.
  7. Bein T, Grasso S, Moerer O, Quintel M, Guerin C, Deja M, et al. The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia. Intensive Care Med 2016;42:699-711.
  8. Braz HLB, Silveira JAM, Marinho AD, de Moraes MEA, Moraes Filho MO, Monteiro HSA, 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;56:106119.
  9. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020;395:565-74.
  10. Morse JS, Lalonde T, Xu S, Liu WR. Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV. Chembiochem 2020;21:730-8.
  11. Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020;9:221-36.
  12. Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des 2011;7:146-57.
  13. Liu X, Zhang B, Jin Z, Yang H, Rao Z. Crystal structure of COVID-19 main protease in complex with an inhibitor N3. Protein DataBank, 2020.
  14. Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, et al. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem 2004;279:17996-8007.
  15. Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 2020;181:894-904.e9.
  16. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785-91.
  17. Lii JH, Allinger NL. Molecular mechanics. The MM3 force field for hydrocarbons. 3. The van der Waals’ potentials and crystal data for aliphatic and aromatic hydrocarbons, J Am Chem Soc 1989;111:8576-82.
  18. Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol 2016;24:490-502.
  19. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020;181:271-80.e8.
  20. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-3.
  21. Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012;4:1011-33.
  22. Kandeel M, Al-Nazawi M. Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease. Life Sci 2020;251:117627.
  23. Gurung AB, Ali MA, Lee J, Farah MA, Al-Anazi KM. Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 Mpro enzyme through in silico approach. Life Sci 2020;255:117831.
  24. Zhang DH, Wu KL, Zhang X, Deng SQ, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med 2020;18:152-8.
  25. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 2020;395:1695-704.
  26. Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ, et al. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent Sci 2020;6:315-31.
  27. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.
  28. Musarrat F, Chouljenko V, Dahal A, Nabi R, Chouljenko T, Jois SD, et al. The anti-HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV-2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID-19 infections. J Med Virol 2020;92:2087-95.
  29. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71.
  30. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, 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;56:105949.
  31. Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, Miller MC, Abraham GM, Obley AJ, et al. Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19 Ann Intern Med. 2020:M20-3862.
  32. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020;369:m1849.
  33. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med 2018;46:e825-73.
  34. Koyuncu İ, Durgun M, Yorulmaz N, Toprak S, Gonel A, Bayraktar N, et al. Molecular docking demonstration of the liquorice chemical molecules on the protease and ACE2 of COVID-19 virus. Current Enzyme Inhibition 2021;7:98-110.
  35. Ozturk H, Yorulmaz N, Durgun M, Basoglu H. In silico investigation of Alliin as potential activator for AMPA receptor. Biomed Phys Eng Express 2021;8.

Copyright and license

Copyright © 2021 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

How to cite?

1.
Büyükfırat E, Durgun M, Yorulmaz N, Koyuncu İ, Karahan MA, Gonel A, et al. Investigation of Interactions Between Sedative, Analgesic and Anaesthetic Drugs with SARS-CoV-2, ACE-2 and SARS-CoV-2- ACE-2 Complex by Molecular Docking Method. Turk J Intensive Care. 2021;19:8-32. https://doi.org/10.4274/tybd.galenos.2021.69885