Screening Of Angiotensin-Converting Enzyme-2 And Furin  Inhibitors As Drug Leads Against Sars-Cov2

Jesvin Bency

doi:10.48165/

Authors

Jesvin Bency Department of Microbiology, Muslim Arts College (Affiliated to Manonmaniam Sundaranar University), Thiruvithancode, Kanyakumari - 629 174, Tamilnadu (India)

DOI:

https://doi.org/10.48165/

Keywords:

ACE2 inhibitors, captopril, furin inhibitors, 4-hydroxycoumarin, SARS-CoV2

Abstract

A database of angiotensin-converting enzyme-2 (ACE2) and furin inhibitors were selected as ligands to screen them as drug leads against SARS CoV2. The methodology employed for screening the inhibitors entailed the use of ADMET SAR server, which facilitated the assessment of drug likeliness, absorption, distribution, metabolism, excretion, and toxicity analysis. Molecular docking analysis was done by using AutoDock Vinasoftware, and it revealed that three potential inhibitors viz., captopril, nicotianamine, and perindopril, exhibited strong binding affinity within the active site of ACE2 protein. Captopril exhibited highest binding affinity of -5.5 kcal mol-1to ACE2 protein with low dock score of -26.074. 4-hydroxycoumarin showed strongest binding with furin active site residues with a binding score of -6.8 kcal mol-1followed by scopoletin and barlerin whose binding scores were slightly lower than 4-hydroxycoumarin. All the 3 ligands showed strong hydrogen binding with conserved Trp-531. The inhibitor 4-hydroxycoumarin exhibited binding with furin involving the amino acid residues Glu-271, Gln-488, Asn-310, Pro-266, Ala-532, and Trp-531. The study revealed that ACE2 and furin inhibitors can serve as lead molecules for optimization and drug development against SARS CoV2. The study has signifi cance in the exploration and development of effective drugs against coronavirus.

Downloads

Download data is not yet available.

References

Albuquerque, D., Nihei, J., Cardillo, F. and Singh, R. 2010. The ACE inhibitors enalapril and captopril modulate cytokine responses in Balb/c and C57Bl/6 normal mice and increase CD4 + CD103 + CD 25 negative splenic T cell numbers. Cellular Immunology, 260(2): 92-97.

ACE2 and furin inhibitors against SARS-CoV2 259

Andricopulo, A.D., Salum, L.B. and Abraham, D.J. 2009. Structure-based drug design strategies in medicinal chemistry. Current Topics in Medicinal Chemistry, 9(9): 771-790. El Zowalaty, M.E. and Järhult, J.D. 2020. From SARS to COVID-19: A previously unknown SARS related coronavirus (SARS-CoV-2) of pandemic potential infecting humans – Call for a one health approach. One Health, 9: 100124. [https://doi.org/10.1016/j.onehlt.2020.100124]. Guan, W.J., Ni, Z.Y., Hu, Y., Liang, W.H., Ou, C.Q., He, J.X., Liu, L., Shan, H., Lei, C.L., Hui, D.S. and Du, B. 2020. Clinical characteristics of coronavirus disease 2019 in China. New England Journal of Medicine, 382(18): 1708-1720.

Hardes, K., Becker, G.L., Lu, Y., Dahms, S.O., Köhler, S., Beyer, W., Sandvig, K., Yamamoto, H., Lindberg, I., Walz, L., von Messling, V., Than, M.E., Garten, W. and Steinmetzer, T. 2015. Novel furin inhibitors with potent anti‐infectious activity. ChemMedChem, 10(7): 1218-1231.

Hasan, A., Paray, B.A., Hussain, A., Qadir, F.A., Attar, F., Aziz, F.M., Sharifi, M., Derakhshankhah, H., Rasti, B., Mehrabi, M. and Shahpasand, K. 2021. A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin. Journal of Biomolecular Structure and Dynamics, 39(8): 3025-3033.

Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A. and Müller, M.A. 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2): 271-280.

Huang, L., Sexton, D.J., Skogerson, K., Devlin, M., Smith, R., Sanyal, I., Parry, T., Kent, R., Enright, J., Wu, Q.L. and Conley, G. 2003. Novel peptide inhibitors of angiotensin-converting enzyme 2. Journal of Biological Chemistry, 278(18): 15532-15540.

Jahn, A., Hinselmann, G., Fechner, N. and Zell, A. 2009. Optimal assignment methods for ligand based virtual screening. Journal of Cheminformatics, 1(1): 1-23.

Lavecchia, A. and Di Giovanni, C. 2013. Virtual screening strategies in drug discovery: A critical review. Current Medicinal Chemistry, 20(23): 2839-2860.

Li, W., Moore, M.J., Vasilieva, N., Sui, J., Wong, S.K., Berne, M.A., Somasundaran, M., Sullivan, J.L., Luzuriaga, K., Greenough, T.C. and Choe, H. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 426(6965): 450-454.

Luchini, A.C., Rodrigues-Orsi, P., Cestari, S.H., Seito, L.N., Witaicenis, A., Pellizzon, C.H. and Di Stasi, L.C. 2008. Intestinal anti-inflammatory activity of coumarin and 4-hydroxycoumarin in the trinitrobenzenesulphonic acid model of rat colitis. Biological and Pharmaceutical Bulletin, 31(7): 1343-1350.

Lythgoe, M.P. and Middleton, P. 2020. Ongoing clinical trials for the management of the COVID-19 pandemic. Trends in Pharmacological Sciences, 41(6): 363-382.

Maza, M.D.C., Úbeda, M., Delgado, P., Horndler, L., Llamas, M.A., van Santen, H.M., Alarcón, B., Abia, D., García-Bermejo, L., Serrano-Villar, S. and Bastolla, U. 2022. ACE2 serum levels as predictor of infectability and outcome in COVID-19. Frontiers in Immunology, 13: 1062. [https://doi.org/10.3389/fimmu.2022.836516].

Mbikay, M., Sirois, F., Yao, J., Seidah, N.G. and Chretien, M. 1997. Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. British Journal of Cancer, 75(10): 1509-1514.

Mortaz, E., Jamaati, H., Roofchayee, N.D., Sheikhzade, H., Mirenayat, M., Sadeghi, M., Lookzadeh, S., Dezfuli, N.K., Folkerts, G., Mumby, S. and Garssen, J. 2022. Decreased serum levels of angiotensin converting enzyme (ACE)2 and enhanced cytokine levels with severity of COVID 19: normalisation upon disease recovery. Heliyon, 8(2): p.e08957. [https://doi.org/10.1016/j.heliyon.2022.e08957].

Peng, H., Carretero, O.A., Vuljaj, N., Liao, T.D., Motivala, A., Peterson, E.L. and Rhaleb, N.E. 2005. Angiotensin-converting enzyme inhibitors: A new mechanism of action. Circulation, 112(16): 2436-2445.

Jesvin Bency

Shapiro, S. and Sherwin, B.T. 1943. The use of dicumarol [3, 3'-methylenebis (4-hydroxycoumarin)] in embolization. Report of five cases. The New York Medical Journal, 43: 45-52. Shoichet, B.K. 2004. Virtual screening of chemical libraries. Nature, 432(7019): 862-865. Subramaniam, S., Mehrotra, M. and Gupta, D. 2008. Virtual high throughput screening (vHTS) - A perspective. Bioinformation, 3(1): 14. [https://doi.org/10.6026%2F97320630 003014]. Tabassum, A., Iqbal, M.S., Sultan, S., Alhuthali, R.A., Alshubaili, D.I., Sayyam, R.S., Abyad, L.M., Qasem, A.H. and Arbaeen, A.F. 2022. Dysregulated Bradykinin: Mystery in the pathogenesis of COVID-19. Mediators of Inflammation, 2022. [https://doi.org/10.1155/2022/7423537]. Teralı, K., Baddal, B. and Gülcan, H.O. 2020. Prioritizing potential ACE2 inhibitors in the COVID 19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment. Journal of Molecular Graphics and Modelling, 100: 107697. [https://doi.org/10.1016/j.jmgm.2020.107697].

Verdecchia, P., Cavallini, C., Spanevello, A. and Angeli, F. 2020. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. European Journal of Internal Medicine, 76: 14-20. Verdecchia, P., Reboldi, G., Cavallini, C., Mazzotta, G. and Angeli, F. 2020. ACE-inhibitors,

angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus. Giornale Italiano di Cardiologia, 21(5): 321-327.

Villoutreix, B.O., Renault, N., Lagorce, D., Sperandio, O., Montes, M. and Miteva, M.A. 2007. Free resources to assist structure-based virtual ligand screening experiments. Current Protein and Peptide Science, 8(4): 381-411.

Walls, A.C., Park, Y.J., Tortorici, M.A., Wall, A., McGuire, A.T. and Veesler, D. 2020. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 181(2): 281-292. Wang, Y., Zhang, D., Du, G., Du, R., Zhao, J., Jin, Y., Fu, S., Gao, L., Cheng, Z., Lu, Q. and Hu, Y. 2020. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo controlled, multicentre trial. The Lancet, 395(10236): 1569-1578.