•  
  •  
 

Indonesian Journal of Medical Chemistry and Bioinformatics

Abstract

The SARS-Coronavirus 2 (SARS-CoV-2) outbreak is a serious global public health threat. Researchers around the world are conducting mass research to control this epidemic, starting from the discovery of vaccines, to new drugs that have specific activities as antivirals. Drug repurposing is a potential method of using drugs with known activity for reuse as COVID-19 therapy. This method has the advantage that it can reduce costs and also the duration in the development of potential drugs. The initial step in drug repurposing can be done computationally to determine the effectiveness and specificity of the drug on the target protein. Molecular docking analysis can see the specific interactions of potential compounds with target proteins by analyzing the energy of the bonds formed. The spike protein of SARS-CoV-2 is a major target in the design and discovery of new drugs for the treatment of Covid-19 disease. In addition, transmembrane protein serine protease (TMPRSS2) from host cells has been shown to have an important role in the proteolytic cleavage of viral spike protein to the ACE2 receptor present in human cells. Based on screening studies, it is known that there are several drugs that have been established that have the potential to inhibit the SARS-CoV-2 transfection mechanism into host cells. 10 potential drug candidates used in this study namely Arbecacin, Bromhexine hydrochloride, Hydroxychloroquine, Camostat mesylate, Darunavir, Dequalinium, Fleroxacin, Lopinavir, Remdesivir, and Octopamine were used in molecular docking. Docking analysis revealed that there were three potential compounds, namely Bromhexine hydrochloride, Camostat mesylate and Octopamine with low binding affinity and inhibition constants. Based on the docking result, Camostat mesylate as the best candidate has a high specific binding affinity for the Ser441 and Asp435 residues present in the TMPRSS2 catalytic triad. Thus, these results reveal the mechanism of inhibition of TMPRSS2 by the known inhibitor Camostat mesylate in detail at the molecular level. Where, Camostat mesylate has a strong bond. This structural information could also be useful for designing and discovering new inhibitors of TMPRSS2, which may be useful for preventing the entry of SARS-CoV 2 into human cells.

Bahasa Abstract

Wabah SARS-Coronavirus 2 (SARS-CoV-2) adalah ancaman kesehatan masyarakat global yang serius. Para peneliti di seluruh dunia sedang melakukan penelitian massal untuk mengendalikan epidemi ini, mulai dari penemuan vaksin, hingga obat baru yang memiliki aktivitas spesifik sebagai antivirus. Penggunaan kembali obat adalah metode potensial untuk menggunakan obat-obatan dengan aktivitas yang diketahui dapat digunakan kembali sebagai terapi COVID-19. Metode ini memiliki kelebihan yaitu dapat menekan biaya dan juga durasi dalam pengembangan obat potensial. Langkah awal dalam repurposing obat dapat dilakukan secara komputasi untuk menentukan efektivitas dan spesifisitas obat pada protein target. Analisis molekuler docking dapat melihat interaksi spesifik senyawa potensial dengan protein target dengan menganalisis energi ikatan yang terbentuk. Protein lonjakan SARS-CoV-2 adalah target utama dalam desain dan penemuan obat baru untuk pengobatan penyakit Covid-19. Selain itu, protein serin protease transmembran (TMPRSS2) dari sel inang telah terbukti memiliki peran penting dalam pembelahan proteolitik protein lonjakan virus ke reseptor ACE2 yang ada dalam sel manusia. Berdasarkan studi penapisan, diketahui ada beberapa obat yang telah ditetapkan berpotensi menghambat mekanisme transfeksi SARS-CoV-2 ke dalam sel inang. 10 kandidat obat potensial yang digunakan dalam penelitian ini yaitu Arbecacin, Bromhexine hydrochloride, Hydroxychloroquine, Camostat mesylate, Darunavir, Dequalinium, Fleroxacin, Lopinavir, Remdesivir, dan Octopamine digunakan dalam molecular docking. Analisis docking mengungkapkan bahwa ada tiga senyawa potensial, yaitu Bromhexine hidroklorida, Camostat mesylate dan Octopamine dengan afinitas pengikatan dan konstanta penghambatan yang rendah. Camostat mesylate sebagai kandidat terbaik memiliki ikatan spesifik dengan afinitas tinggi untuk residu Ser441 dan Asp435 yang ada dalam triad katalitik TMPRSS2. Dengan demikian, hasil ini mengungkapkan mekanisme penghambatan TMPRSS2 oleh inhibitor Camostat mesylate yang diketahui secara rinci pada tingkat molekuler. Dimana, Camostat mesylate memiliki ikatan yang kuat. Informasi struktural ini juga dapat berguna untuk merancang dan menemukan inhibitor baru TMPRSS2, yang mungkin berguna untuk mencegah masuknya SARS-CoV-2 ke dalam sel manusia.

References

1. Zhou P, Yang X Lou, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature [Internet]. 2020;579(7798):270–3. Available from: http://dx.doi.org/10.1038/s41586-020-2012-7

2. Gugus Tugas Percepatan Penanganan Covid-19. Beranda _ Covid19 [Internet]. 2021. 2021. Available from: https://covid19.go.id/

3. Schoeman D, Fielding BC, Arias-Reyes C, Zubieta-DeUrioste N, Poma-Machicao L, Aliaga-Raudan F, et al. Journal Pre-proof Does the pathogenesis of SAR-CoV-2 virus decrease at high-altitude? Does the pathogenesis of SAR-CoV-2 virus decrease at high-altitude? Corresponding authors. Cell Res. 2020;9(1):278–80.

4. Hasöksüz M, Kiliç S, Saraç F. Coronaviruses and sars-cov-2. Turkish J Med Sci. 2020;50(SI-1):549–56.

5. Harrison AG, Lin T, Wang P. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends Immunol [Internet]. 2020;41(12):1100–15. Available from: https://doi.org/10.1016/j.it.2020.10.004

6. Baby K, Maity S, Mehta CH, Suresh A, Nayak UY, Nayak Y. SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study. Eur J Pharmacol. 2021;896:1–11.

7. Kyrieleis OJ., Huber R, Madison E., Jacob U. Crystal structure of type II transmembrane serine proteinase. PDB Entry. 2018.

8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.

9. Bittmann S, Weissenstein A, Billalo G, Alieva EM, Luchter E. Simultaneous Treatment of COVID-19 With Serine Protease, Bitman.pdf. J Clin Med Res. 2020;12(5):320–2.

10. Huggins DJ. Structural analysis of experimental drug binding to the SARS-CoV-2 target TMPRSS2. J Mol Graph Model. 2020;100:1–7.

11. Yousefifard M, Zali A, Ali KM, Neishaboori AM, Zarghi A, Hosseini M, et al. Antiviral Therapy inManagement of COVID-19: a Systematic Review on Current Evidence. Arch Acad Emerg Med. 2020;8(1):1–9.

12. Supriya T, Shankar M, Kavya Lalitha S, Dastgiri J, Niranjan Babu M. A Over View on Molecular Docking. Am J Biol Pharm Res [Internet]. 2016;3(2):83–9. Available from: www.mcmed.us/journal/ajbpr

13. Weiss J, Bajraktari-Sylejmani G, Haefeli WE. Low risk of the TMPRSS2 inhibitor camostat mesylate and its metabolite GBPA to act as perpetrators of drug-drug interactions. Chem Biol Interact [Internet]. 2021;338(January):109428. Available from: https://doi.org/10.1016/j.cbi.2021.109428

14. Singh TU, Parida S, Lingaraju MC, Kesavan M, Kumar D, Singh RK. Drug repurposing approach to fight COVID-19. Pharmacol Reports [Internet]. 2020;72(6):1479–508. Available from: https://doi.org/10.1007/s43440-020-00155-6

15. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature [Internet]. 2020;582(7811):289–93. Available from: http://dx.doi.org/10.1038/s41586-020-2223-y

16. Idris MO, Yekeen AA, Alakanse OS, Durojaye OA. Computer-aided screening for potential TMPRSS2 inhibitors: a combination of pharmacophore modeling, molecular docking and molecular dynamics simulation approaches. J Biomol Struct Dyn [Internet]. 2020;39(15):1–19. Available from: https://doi.org/10.1080/07391102.2020.1792346

17. Han Y, Král P. Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2. ACS Nano. 2020;14(4):5143–7.

18. Sheahan TP, Sims AC, Zhou S, Graham RL, Hill CS, Leist SR, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus. bioRxiv. 2020;5883:1–20.

19. Hoffmann M, Hofmann-Winkler H, Smith JC, Krüger N, Arora P, Sørensen LK, et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 2021;65(Ivm).

20. Hoffmann M, Hofmann-Winkler H, Smith JC, Krüger N, Arora P, Sørensen LK, et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 2021;65.

21. Abo-zeid Y, Ismail NS, McLean GR, Hamdy NM. A molecular docking study repurposes FDA approved iron oxide nanoparticles to treat and control COVID-19 infection. Eur J Pharm Sci [Internet]. 2020;153(July):105465. Available from: https://doi.org/10.1016/j.ejps.2020.105465

22. Shiryaev SA, Chernov A V., Golubkov VS, Thomsen ER, Chudin E, Chee MS, et al. High-Resolution Analysis and Functional Mapping of Cleavage Sites and Substrate Proteins of Furin in the Human Proteome. PLoS One. 2013;8(1):1–12.

23. Sonawane KD, Barale SS, Dhanavade MJ, Waghmare SR, Nadaf NH, Kamble SA, et al. Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach. Informatics Med Unlocked [Internet]. 2021;24(February):100597. Available from: https://doi.org/10.1016/j.imu.2021.100597

24. Hempel T, Raich L, Olsson S, Azouz NP, Klingler AM, Rothenberg ME, et al. Molecular mechanism of SARS-CoV-2 cell entry inhibition via TMPRSS2 by Camostat and Nafamostat mesylate. bioRxiv. 2020;(Md).

25. Li K, Meyerholz DK, Bartlett JA, McCray PB. The tmprss2 inhibitor nafamostat reduces sars-cov-2 pulmonary infection in mouse models of covid-19. MBio. 2021;12(4).

26. Azimi A. TMPRSS2 inhibitors, Bromhexine, Aprotinin, Camostat and Nafamostat as potential treatments for COVID-19. 2020;

27. Hosoya M, Matsuyama S, Baba M, Suzuki H, Shigeta S. Effects of Protease Inhibitors on Replication of Various Myxoviruses. Antimicrob Agent Chemother. 1992;36(7):1432–6.

28. Ota S, Hara Y, Kanoh S, Shinoda M, Kawano S, Fujikura Y, et al. Acute eosinophilic pneumonia caused by camostat mesilate: The first case report. Respir Med Case Reports [Internet]. 2016;19:21–3. Available from: http://dx.doi.org/10.1016/j.rmcr.2016.06.005

29. Yamaya M, Shimotai Y, Hatachi Y, Lusamba Kalonji N, Tando Y, Kitajima Y, et al. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther [Internet]. 2015;33:66–74. Available from: http://dx.doi.org/10.1016/j.pupt.2015.07.001

30. Iki Y, Hata A, Fukuyama M, Yoshioka T, Watanabe K, Asari S, et al. Successful conservative treatment of mycotic pulmonary artery aneurysms caused by mrsa bacteremia. Pediatrics. 2019;144(5).

31. Fu Q, Zheng X, Zhou Y, Tang L, Chen Z, Ni S. Re-recognizing bromhexine hydrochloride: pharmaceutical properties and its possible role in treating pediatric COVID-19. Eur J Clin Pharmacol. 2021;77(2):261–3.

32. Baildya N, Ghosh NN, Chattopadhyay AP. Inhibitory activity of hydroxychloroquine on COVID-19 main protease: An insight from MD-simulation studies. J Mol Struct [Internet]. 2020;1219:128595. Available from: https://doi.org/10.1016/j.molstruc.2020.128595

33. Hussein RK, Elkhair HM. Molecular docking identification for the efficacy of some zinc complexes with chloroquine and hydroxychloroquine against main protease of COVID-19. J Mol Struct. 2021;1231.

34. Sonawane KD, Barale SS, Dhanavade MJ, Waghmare SR, Nadaf NH, Kamble SA, et al. Homology modeling and docking studies of TMPRSS2 with experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-Coronavirus-2. ChemRxiv. 2020;(April).

35. Lin S, Shen R, Guo X. Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases. bioRxiv [Internet]. 2020;1–11. Available from: https://doi.org/10.1101/2020.01.31.929695

36. Elmorsy MA, El-Baz AM, Mohamed NH, Almeer R, Abdel-Daim MM, Yahya G. In silico screening of potent inhibitors against COVID-19 key targets from a library of FDA-approved drugs. Environ Sci Pollut Res. 2021;

37. Yu R, Li P. Computational and experimental studies on the inhibitory mechanism of hydroxychloroquine on hERG. Toxicology [Internet]. 2021;458(March):152822. Available from: https://doi.org/10.1016/j.tox.2021.152822

38. Cheke RS. 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.

39. Choi JP, Kim HJ, Han J, Park S, Han JJ. Foistar®(Camostat mesylate) associated with the significant decrease in CRP levels compared to Kaletra®(Lopinavir/Ritonavir) treatment in Korean mild COVID-19 pneumonic patients. medRxiv. 2020;21(1):1–15.

40. Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020;253(March).

41. Kandeel M, Al-Nazawi M. Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease. Life Sci [Internet]. 2020;251(March):117627. Available from: https://doi.org/10.1016/j.lfs.2020.117627

42. Hasoksuz M, Sreevatsan S, Cho K, Hoet AE, Saif LJ. Molecular analysis of the S1 subunit of the spike glycoprotein of respiratory and enteric bovine coronavirus isolates. Virus Res. 2020;84(January):101–9.

43. Nieto-Torres JL, DeDiego ML, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Fernandez-Delgado R, et al. Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis. PLoS Pathog. 2014;10(5).

44. Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ. 2020;371:1–6.

45. Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, et al. Full wwPDB X-ray Structure Validation Report 4DKL. Vol. 7. 2012.

46. Zhao H, Huang D. Hydrogen bonding penalty upon ligand binding. PLoS One. 2011;6(6).

47. Domínguez-Villa FX, Durán-Iturbide NA, Ávila-Zárraga JG. Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl)indol-4-ones: Potential inhibitors of SARS CoV-2 main protease. Bioorg Chem. 2021;106(October 2020).

48. Pollastri MP. Overview on the rule of five. Curr Protoc Pharmacol. 2010;(SUPPL. 49):1–8.

49. Ghose AK, Herbertz T, Hudkins RL, Dorsey BD, Mallamo JP. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem Neurosci. 2012;3(1):50–68.

Download

Share

COinS