Home In silico design of ACE2 mutants for competitive binding of SARS-CoV-2 receptor binding domain with hACE2
Article
Licensed
Unlicensed Requires Authentication

In silico design of ACE2 mutants for competitive binding of SARS-CoV-2 receptor binding domain with hACE2

  • Theam Soon Lim and Yee Siew Choong ORCID logo EMAIL logo
Published/Copyright: April 1, 2022
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Physical Sciences Reviews
From the journal Physical Sciences Reviews Volume 8 Issue 10

Abstract

The receptor binding motif (RBM) within the S-protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been touted as one of the main targets for vaccine/therapeutic development due to its interaction with the human angiotensin II converting enzyme 2 (hACE2) to facilitate virus entry into the host cell. The mechanism of action is based on the disruption of binding between the RBM and the hACE2 to prevent virus uptake for replication. In this work, we applied in silico approaches to design specific competitive binders for SARS-CoV-2 S-protein receptor binding motif (RBM) by using hACE2 peptidase domain (PD) mutants. Online single point mutation servers were utilised to estimate the effect of PD mutation on the binding affinity with RBM. The PD mutants were then modelled and the binding free energy was calculated. Three PD variants were designed with an increased affinity and interaction with SARS-CoV-2-RBM. It is hope that these designs could serve as the initial work for vaccine/drug development and could eventually interfere the preliminary recognition between SARS-CoV-2 and the host cell.

Keywords: hACE2 peptidase domain (PD); specific binders for SARS-CoV-2 receptor binding motif (RBM); structure-based rational design
Corresponding author: Yee Siew Choong, Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia, E-mail:

Funding source: Malaysia Minsitry of Higher Education Fundamental Research Grant Scheme

Award Identifier / Grant number: FRGS/1/2018/STG05/USM/02/1; 203/CIPPM/6711680

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by Fundamental Research Grant Scheme (FRGS/1/2018/STG05/USM/02/1; 203/CIPPM/6711680) from Malaysia Ministry of Education.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

1. Du, L, Tai, W, Zhou, Y, Jiang, S. Vaccines for the prevention against the threat of MERS-CoV. Expert Rev Vaccines 2016;15:1123–34. https://doi.org/10.1586/14760584.2016.1167603.Search in Google Scholar PubMed PubMed Central

2. Zhou, Y, Jiang, S, Du, L. Prospects for a MERS-CoV spike vaccine. Expert Rev Vaccines 2018;17:677–86. https://doi.org/10.1080/14760584.2018.1506702.Search in Google Scholar PubMed PubMed Central

3. Hoffmann, M, Kleine-Weber, H, Schroeder, S, Kruger, 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. https://doi.org/10.1016/j.cell.2020.02.052.Search in Google Scholar PubMed PubMed Central

4. Li, W, Moore, MJ, Vasilieva, N, Sui, J, Wong, SK, Berne, MA, et al.. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450–4. https://doi.org/10.1038/nature02145.Search in Google Scholar PubMed PubMed Central

5. Tai, W, He, L, Zhang, X, Pu, J, Voronin, D, Jiang, S, et al.. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol 2020;17:613–20. https://doi.org/10.1038/s41423-020-0400-4.Search in Google Scholar PubMed PubMed Central

6. Walls, AC, Park, YJ, Tortorici, MA, Wall, A, McGuire, AT, Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281–92. https://doi.org/10.1016/j.cell.2020.02.058.Search in Google Scholar PubMed PubMed Central

7. Wong, SK, Li, W, Moore, MJ, Choe, H, Farzan, M. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem 2004;279:3197–201. https://doi.org/10.1074/jbc.c300520200.Search in Google Scholar PubMed PubMed Central

8. 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. https://doi.org/10.1126/science.abb2507.Search in Google Scholar PubMed PubMed Central

9. Lu, G, Wang, Q, Gao, GF. Bat-to-human: spike features determining ’host jump’ of coronaviruses SARS-CoV, MERS-CoV, and beyond. Trends Microbiol 2015;23:468–78. https://doi.org/10.1016/j.tim.2015.06.003.Search in Google Scholar PubMed PubMed Central

10. Shang, J, Wan, Y, Luo, C, Ye, G, Geng, Q, Auerbach, A, et al.. Cell entry mechanism of SARS-CoV-2. Proc Natl Acad Sci U S A 2020;117:11727–34. https://doi.org/10.1073/pnas.2003138117.Search in Google Scholar PubMed PubMed Central

11. Shang, J, Ye, G, Shi, K, Wan, Y, Luo, C, Aihara, H, et al.. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020;581:221–4. https://doi.org/10.1038/s41586-020-2179-y.Search in Google Scholar PubMed PubMed Central

12. Li, F, Li, W, Farzan, M, Harrison, SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 2005;309:1864–8. https://doi.org/10.1126/science.1116480.Search in Google Scholar PubMed

13. Liu, S, Xiao, G, Chen, Y, He, Y, Niu, J, Escalante, CR, et al.. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet 2004;363:938–47. https://doi.org/10.1016/s0140-6736(04)15788-7.Search in Google Scholar

14. Raj, VS, Mou, H, Smits, SL, Dekkers, DH, Muller, MA, Dijkman, R, et al.. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013;495:251–4. https://doi.org/10.1038/nature12005.Search in Google Scholar PubMed PubMed Central

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;181:1–11. https://doi.org/10.1016/j.cell.2020.03.045.Search in Google Scholar PubMed PubMed Central

16. Lan, J, Ge, J, Yu, J, Shan, S, Zhou, H, Fan, S, et al.. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215–20. https://doi.org/10.1038/s41586-020-2180-5.Search in Google Scholar PubMed

17. Chen, Y, Guo, Y, Pan, Y, Zhao, ZJ. Structure analysis of the receptor binding of 2019-nCoV. Biochem Biophys Res Commun 2020;525:135–40. https://doi.org/10.1016/j.bbrc.2020.02.071.Search in Google Scholar PubMed PubMed Central

18. Wan, Y, Shang, J, Graham, R, Baric, RS, Li, F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS Coronavirus. J Virol 2020;94:e00127-20. https://doi.org/10.1128/JVI.00127-20.Search in Google Scholar PubMed PubMed Central

19. Petukh, M, Dai, L, Alexov, E. SAAMBE: webserver to predict the charge of binding free energy caused by amino acids mutations. Int J Mol Sci 2016;17:547. https://doi.org/10.3390/ijms17040547.Search in Google Scholar PubMed PubMed Central

20. Dehouck, Y, Kwasigroch, JM, Rooman, M, Gilis, D. BeAtMuSiC: prediction of changes in protein-protein binding affinity on mutations. Nucleic Acids Res 2013;41:W333-39. https://doi.org/10.1093/nar/gkt450.Search in Google Scholar PubMed PubMed Central

21. Yugandhar, K, Gromiha, MM. Protein-protein binding affinity prediction from amino acid sequence. Bioinformatics 2014;30:3583–9. https://doi.org/10.1093/bioinformatics/btu580.Search in Google Scholar PubMed

22. Rigsby, RE, Parker, AB. Using the PyMOL application to reinforce visual understanding of protein structure. Biochem Mol Biol Educ 2016;44:433–7. https://doi.org/10.1002/bmb.20966.Search in Google Scholar PubMed

23. Xue, LC, Rodrigues, JP, Kastritis, PL, Bonvin, AM, Vangone, A. PRODIGY: a web server for predicting the binding affinity of protein-protein complexes. Bioinformatics 2016;32:3676–8. https://doi.org/10.1093/bioinformatics/btw514.Search in Google Scholar PubMed

24. Chen, J, Feng, S, Xu, Y, Huang, X, Zhang, J, Chen, J, et al.. Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase. RSC Med Chem 2020;11:148–54. https://doi.org/10.1039/c9md00473d.Search in Google Scholar PubMed PubMed Central

25. Yu, Y, Deng, YQ, Zou, P, Wang, Q, Dai, Y, Du, L, et al.. A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat Commun 2017;8:15672. https://doi.org/10.1038/ncomms15672.Search in Google Scholar PubMed PubMed Central

26. Huang, X, Li, M, Xu, Y, Zhang, J, Meng, X, An, X, et al.. Novel gold nanorod-based HR1 peptide inhibitor for Middle East Respiratory Syndrome coronavirus. ACS Appl Mater Interfaces 2019;11:19799–807. https://doi.org/10.1021/acsami.9b04240.Search in Google Scholar PubMed

27. Xiong, S, Borrego, P, Ding, X, Zhu, Y, Martins, A, Chong, H, et al.. A helical short-peptide fusion inhibitor with highly potent activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus. J Virol 2017;91:e01839-16. https://doi.org/10.1128/JVI.01839-16.Search in Google Scholar PubMed PubMed Central

28. Chung, PY, Khanum, R. Antimicrobial peptides as potential anti-biofilm agents against multidrug-resistant bacteria. J Microbiol Immunol Infect 2017;50:405–10. https://doi.org/10.1016/j.jmii.2016.12.005.Search in Google Scholar PubMed

29. do Nascimento Dias, J, de Souza Silva, C, de Araujo, AR, Souza, JMT, de Holanda Veloso Junior, PH, Cabral, WF, et al.. Mechanisms of action of antimicrobial peptides ToAP2 and NDBP-5.7 against Candida albicans planktonic and biofilm cells. Sci Rep 2020;10:10327. https://doi.org/10.1038/s41598-020-67041-2.Search in Google Scholar PubMed PubMed Central

30. Hacioglu, M, Oyardi, O, Bozkurt-Guzel, C, Savage, PB. Antibiofilm activities of ceragenins and antimicrobial peptides against fungal-bacterial mono and multispecies biofilms. J Antibiot 2020;73:455–62. https://doi.org/10.1038/s41429-020-0299-0.Search in Google Scholar PubMed

31. Sabia Junior, EF, Menezes, LFS, de Araujo, IFS, Schwartz, EF. Natural occurrence in venomous arthropods of antimicrobial peptides active against protozoan parasites. Toxins 2019;11:563. https://doi.org/10.3390/toxins11100563.Search in Google Scholar PubMed PubMed Central

32. Dijksteel, GS, Ulrich, MMW, Middelkoop, E, Boekema, BKHL. Review: lessons learned from clinical trials using antimicrobial peptides (AMPs). Front Microbiol 2021;12:287. https://doi.org/10.3389/fmicb.2021.616979.Search in Google Scholar PubMed PubMed Central

33. León-Buitimea, A, Garza-Cárdenas, CR, Garza-Cervantes, JA, Lerma-Escalera, JA, Morones-Ramírez, JR. The demand for new antibiotics: antimicrobial peptides, nanoparticles, and combinatorial therapies as future strategies in antibacterial agent design. Front Microbiol 2020;11:1669.10.3389/fmicb.2020.01669Search in Google Scholar PubMed PubMed Central

34. Moretta, A, Scieuzo, C, Petrone, AA, Salvia, R, Manniello, MD, Franco, A, et al.. Antimicrobial peptides: a new hope in biomedical and pharmaceutical fields. Front Cell Infect Microbiol 2021;11:453. https://doi.org/10.3389/fcimb.2021.668632.Search in Google Scholar PubMed PubMed Central

35. Yan, R, Zhang, Y, Li, Y, Xia, L, Guo, Y, Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444–8. https://doi.org/10.1126/science.abb2762.Search in Google Scholar PubMed PubMed Central

36. DeLano, WL. The PyMOL molecular graphics system. San Carlos, CA, USA: DeLano Scientific LLC; 2003.Search in Google Scholar

37. Hussain, M, Jabeen, N, Raza, F, Shabbir, S, Baig, AA, Amanullah, A, et al.. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J Med Virol 2020;92:1580–6. https://doi.org/10.1002/jmv.25832.Search in Google Scholar PubMed PubMed Central

Published Online: 2022-04-01

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Recent endeavors in microbial remediation of micro- and nanoplastics
  4. Metal nanoparticles and its application on phenolic and heavy metal pollutants
  5. The story of nitrogen
  6. Recent development of imidazole derivatives as potential anticancer agents
  7. Indole based prostate cancer agents
  8. Lawsone (2-hydroxy-1,4-naphthaquinone) derived anticancer agents
  9. Small modular nuclear reactors are mostly bad policy
  10. A holistic environmental investigation of complementary energy in Alberta
  11. Green synthesis of various saturated S-heterocyclic scaffolds: an update
  12. Recent advances of heterocycle based anticancer hybrids
  13. Molecular docking and MD: mimicking the real biological process
  14. Synthesis of quinazolinone and quinazoline derivatives using green chemistry approach
  15. Nuclear fusion: the promise of endless energy
  16. Finance for Green Chemistry through Currency Mix
  17. Synthesis of bioactive scaffolds catalyzed by agro-waste-based solvent medium
  18. Recent developments in the green synthesis of biologically relevant cinnolines and phthalazines
  19. Detection of Rapid Eye Movement Behaviour Sleep Disorder using Time and Frequency Analysis of EEG Signal Applied on C4-A1 Channels
  20. Recent developments in C–C bond formation catalyzed by solid supported palladium: a greener perspective
  21. Visible-light-mediated metal-free C–Si bond formation reactions
  22. An overview of quinoxaline synthesis by green methods: recent reports
  23. Naturally occurring, natural product inspired and synthetic heterocyclic anti-cancer drugs
  24. Synthesis of bioactive natural products and their analogs at room temperature – an update
  25. One-pot multi-component synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives as a versatile reagent
  26. Synthesis of new horizons in benzothiazole scaffold and used in anticancer drug development
  27. Triazine based chemical entities for anticancer activity
  28. Modification of kaolinite/muscovite clay for the removal of Pb(II) ions from aqueous media
  29. In silico design of ACE2 mutants for competitive binding of SARS-CoV-2 receptor binding domain with hACE2
  30. Computational study of Cu n AgAu (n = 1–4) clusters invoking DFT based descriptors
  31. Development of an online assessment system to evaluate knowledge on chemical safety and security
  32. Developing a questionnaire for diabetes mellitus type 2 risk effects and precondition factors – multivariate statistical paths
  33. Antioxidant and antibacterial activities of two xanthones derivatives isolated from the leaves extract of Anthocleista schweinfurthii Gilg (Loganiaceae)
  34. The stability increase of α-amylase enzyme from Aspergillus fumigatus using dimethyladipimidate
  35. Sustainability of ameliorative potentials of urea spiked poultry manure biochar types in simulated sodic soils
  36. Cytotoxicity test and antibacterial assay on the compound produced by the isolation and modification of artonin E from Artocarpus kemando Miq.
  37. Effects of alum, soda ash, and carbon dioxide on 40–50 year old concrete wastewater tanks
https://doi.org/10.1515/psr-2021-0136
Keywords for this article
hACE2 peptidase domain (PD); specific binders for SARS-CoV-2 receptor binding motif (RBM); structure-based rational design

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Recent endeavors in microbial remediation of micro- and nanoplastics
  4. Metal nanoparticles and its application on phenolic and heavy metal pollutants
  5. The story of nitrogen
  6. Recent development of imidazole derivatives as potential anticancer agents
  7. Indole based prostate cancer agents
  8. Lawsone (2-hydroxy-1,4-naphthaquinone) derived anticancer agents
  9. Small modular nuclear reactors are mostly bad policy
  10. A holistic environmental investigation of complementary energy in Alberta
  11. Green synthesis of various saturated S-heterocyclic scaffolds: an update
  12. Recent advances of heterocycle based anticancer hybrids
  13. Molecular docking and MD: mimicking the real biological process
  14. Synthesis of quinazolinone and quinazoline derivatives using green chemistry approach
  15. Nuclear fusion: the promise of endless energy
  16. Finance for Green Chemistry through Currency Mix
  17. Synthesis of bioactive scaffolds catalyzed by agro-waste-based solvent medium
  18. Recent developments in the green synthesis of biologically relevant cinnolines and phthalazines
  19. Detection of Rapid Eye Movement Behaviour Sleep Disorder using Time and Frequency Analysis of EEG Signal Applied on C4-A1 Channels
  20. Recent developments in C–C bond formation catalyzed by solid supported palladium: a greener perspective
  21. Visible-light-mediated metal-free C–Si bond formation reactions
  22. An overview of quinoxaline synthesis by green methods: recent reports
  23. Naturally occurring, natural product inspired and synthetic heterocyclic anti-cancer drugs
  24. Synthesis of bioactive natural products and their analogs at room temperature – an update
  25. One-pot multi-component synthesis of diverse bioactive heterocyclic scaffolds involving 6-aminouracil or its N-methyl derivatives as a versatile reagent
  26. Synthesis of new horizons in benzothiazole scaffold and used in anticancer drug development
  27. Triazine based chemical entities for anticancer activity
  28. Modification of kaolinite/muscovite clay for the removal of Pb(II) ions from aqueous media
  29. In silico design of ACE2 mutants for competitive binding of SARS-CoV-2 receptor binding domain with hACE2
  30. Computational study of Cu n AgAu (n = 1–4) clusters invoking DFT based descriptors
  31. Development of an online assessment system to evaluate knowledge on chemical safety and security
  32. Developing a questionnaire for diabetes mellitus type 2 risk effects and precondition factors – multivariate statistical paths
  33. Antioxidant and antibacterial activities of two xanthones derivatives isolated from the leaves extract of Anthocleista schweinfurthii Gilg (Loganiaceae)
  34. The stability increase of α-amylase enzyme from Aspergillus fumigatus using dimethyladipimidate
  35. Sustainability of ameliorative potentials of urea spiked poultry manure biochar types in simulated sodic soils
  36. Cytotoxicity test and antibacterial assay on the compound produced by the isolation and modification of artonin E from Artocarpus kemando Miq.
  37. Effects of alum, soda ash, and carbon dioxide on 40–50 year old concrete wastewater tanks
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 12.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/psr-2021-0136/html
Scroll to top button