Supervised Molecular Dynamics for Exploring the Druggability of the SARS-CoV-2 Spike Protein

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2020 Oct 26

PMID 33103220

Citations 33

Authors

Giuseppe Deganutti

Filippo Prischi

Christopher A Reynolds

Affiliations

Soon will be listed here.

Abstract

The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.

Citing Articles

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References

Xydakis M, Dehgani-Mobaraki P, Holbrook E, Geisthoff U, Bauer C, Hautefort C . Smell and taste dysfunction in patients with COVID-19. Lancet Infect Dis. 2020; 20(9):1015-1016. PMC: 7159875. DOI: 10.1016/S1473-3099(20)30293-0. View

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506. PMC: 7159299. DOI: 10.1016/S0140-6736(20)30183-5. View

Rothan H, Byrareddy S . The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020; 109:102433. PMC: 7127067. DOI: 10.1016/j.jaut.2020.102433. View

Wang W, Tang J, Wei F . Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan, China. J Med Virol. 2020; 92(4):441-447. PMC: 7167192. DOI: 10.1002/jmv.25689. View

Li F . Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu Rev Virol. 2016; 3(1):237-261. PMC: 5457962. DOI: 10.1146/annurev-virology-110615-042301. View

Fehr A, Perlman S . Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015; 1282:1-23. PMC: 4369385. DOI: 10.1007/978-1-4939-2438-7_1. View

Collins A, Knobler R, Powell H, Buchmeier M . Monoclonal antibodies to murine hepatitis virus-4 (strain JHM) define the viral glycoprotein responsible for attachment and cell--cell fusion. Virology. 1982; 119(2):358-71. PMC: 7130542. DOI: 10.1016/0042-6822(82)90095-2. View

Jiang F, Deng L, Zhang L, Cai Y, Cheung C, Xia Z . Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19). J Gen Intern Med. 2020; 35(5):1545-1549. PMC: 7088708. DOI: 10.1007/s11606-020-05762-w. View

Abraham S, Kienzle T, Lapps W, Brian D . Deduced sequence of the bovine coronavirus spike protein and identification of the internal proteolytic cleavage site. Virology. 1990; 176(1):296-301. PMC: 7157924. DOI: 10.1016/0042-6822(90)90257-r. View

10.

Hoffmann M, Kleine-Weber H, Pohlmann S . A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell. 2020; 78(4):779-784.e5. PMC: 7194065. DOI: 10.1016/j.molcel.2020.04.022. View

11.

Walls A, Park Y, Tortorici M, Wall A, McGuire A, Veesler D . Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020; 181(2):281-292.e6. PMC: 7102599. DOI: 10.1016/j.cell.2020.02.058. View

12.

Tikellis C, Thomas M . Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012; 2012:256294. PMC: 3321295. DOI: 10.1155/2012/256294. View

13.

Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N . A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87(5):E1-9. DOI: 10.1161/01.res.87.5.e1. View

14.

Li M, Li L, Zhang Y, Wang X . Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020; 9(1):45. PMC: 7186534. DOI: 10.1186/s40249-020-00662-x. View

15.

Joshi S, Joshi M, Degani M . Tackling SARS-CoV-2: proposed targets and repurposed drugs. Future Med Chem. 2020; 12(17):1579-1601. PMC: 7307730. DOI: 10.4155/fmc-2020-0147. View

16.

Sharma S, Tiwari M, Tiwari V . Therapeutic strategies against autophagic escape by pathogenic bacteria. Drug Discov Today. 2020; 26(3):704-712. DOI: 10.1016/j.drudis.2020.12.002. View

17.

Whisenant J, Burgess K . Blocking Coronavirus 19 Infection via the SARS-CoV-2 Spike Protein: Initial Steps. ACS Med Chem Lett. 2020; 11(6):1076-1078. PMC: 7241730. DOI: 10.1021/acsmedchemlett.0c00233. View

18.

Xiu S, Dick A, Ju H, Mirzaie S, Abdi F, Cocklin S . Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities. J Med Chem. 2020; 63(21):12256-12274. PMC: 7315836. DOI: 10.1021/acs.jmedchem.0c00502. View

19.

Chi X, Yan R, Zhang J, Zhang G, Zhang Y, Hao M . A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science. 2020; 369(6504):650-655. PMC: 7319273. DOI: 10.1126/science.abc6952. View

20.

Pinto D, Park Y, Beltramello M, Walls A, Tortorici M, Bianchi S . Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020; 583(7815):290-295. DOI: 10.1038/s41586-020-2349-y. View