Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis

Juan Carlos Santiago-Jiménez; Gabriel Ramirez-Damaso; Alberto Garcia-Quiroz; Francisco-Caballero; Fray de Landa Castillo-Alvarado

doi:doi:10.11648/j.jddmc.20251104.12

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| Peer-Reviewed

Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis

Juan Carlos Santiago-Jiménez^*

, Gabriel Ramirez-Damaso

, Alberto Garcia-Quiroz

, Francisco-Caballero

, Fray de Landa Castillo-Alvarado

Published in Journal of Drug Design and Medicinal Chemistry (Volume 11, Issue 4)

Received: 24 November 2025 Accepted: 5 December 2025 Published: 29 December 2025

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Abstract

Long COVID, or post-COVID-19, is emerging as a prevalent and complex syndrome affecting a significant percentage of patients who have recovered from the acute phase of SARS-CoV-2 infection. The viral envelope protein (E), a 75 amino acid ion channel, is a crucial structural component involved in viral pathogenesis. This study employs density functional theory (DFT) principles to calculate global reactivity descriptors of the short hydrophilic N-terminal domain of the E protein. The results indicate an ionization potential (IP) of 6.47eV, an electron affinity (EA) of 4.39eV, and a molecular hardness (η) of 1.04eV, suggesting moderate to high chemical reactivity. An electrophilicity (ω) value of 14.17eV reveals a marked tendency to accept electrons. These electronic descriptors, along with the described biological functions of the E protein, such as its role in viral assembly, budding, and modulation of the host inflammatory response, position it as a promising therapeutic target. We also report on the reactivity sites (HOMO-LUMO) present in the short hydrophilic N-terminal domain. Inhibition of the E protein could alter key viral processes and attenuate the immune dysregulation underlying persistent COVID-19, opening new avenues for rational drug design.

Published in	Journal of Drug Design and Medicinal Chemistry (Volume 11, Issue 4)
DOI	10.11648/j.jddmc.20251104.12
Page(s)	63-68
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2025. Published by Science Publishing Group

Keywords

SARS-CoV-2, E Protein, Long COVID-19, DFT, HOMO-LUMO, Global Reactivity Descriptors, Therapeutic Target, Drug Design

References

[1]	Lopez-Sampalo, A. et al. (2022). Persistent COVID-19 syndrome. A narrative review. Revista clinica española. 222(4), 241–250. https://doi.org/10.1016/j.rce.2021.10.003
[2]	Qingfa Wu. et al. (2003). The E Protein is a Multifunctional Membrane Protein of SARS-CoV, Genomics, Proteomics & Bioinformatics, Volume 1, Issue 2, May, Pages 131–144. https://doi.org/10.1016/s1672-0229(03) 01017-9
[3]	Zhou S. et al. (2023). SARS-CoV-2 E protein: Pathogenesis and potential therapeutic development. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 159, 114242. https://doi.org/10.1016/j.biopha.2023.114242
[4]	Gerard Duart. et al. (2020). SARS-CoV-2 envelope protein topology in eukaryotic membranes. Open Biol. 10(9), 200209. https://doi.org/10.1098/rsob.200209
[5]	B. Neitthoffer. et al. (2024). A short sequence in the tail of the SARS-CoV-2 envelope protein controls the accessibility of its PDZ binding motif to the cytoplasm. J Biol Chem. 300(1), 105575. https://doi.org/10.1016/j.jbc.2023.105575
[6]	Kamel W. et al. (2021). Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection. Molecular cell. 81(13), 2851–2867. e7. https://doi.org/10.1016/j.molcel.2021.05.023
[7]	R Marcoleta. et al. (2022). Assessment of seventeen density functionals to estimate the global reactivity of C20 in the framework of the conceptual density functional theory, Chemical Physics Letters, Volume 806, 140005, https://doi.org/10.1016/j.cplett.2022.140005
[8]	Santiago-Jiménez, J. C. et al. (2023). Interaction sites in the receptor-binding domain (RBD) of the spike wild-type SARS-CoV-2 protein of the posaconazole (POS) drug and its quantum–mechanical characterization. MRS Advances 8, 1279–1283. https://doi.org/10.1557/s43580-023-00666-3
[9]	Robert Sedlak et al. (2013). Accuracy of quantum chemical methods for large non-covalent complexes. Journal of Chemical Theory and Computation, vol. 9/Issue 8. https://pubs.acs.org/doi/10.1021/ct400036b
[10]	Perdew, J. P., Burke, K., & Ernzerhof, M. (1996). Generalized gradient approximation made simple. Physical Review Letters, 77(18), 3865–3868. https://doi.org/10.1103/PhysRevLett.77.3865
[11]	Parr, R. G., & Yang, W. (1989). Density-functional theory of atoms and molecules. Oxford University Press. https://doi.org/10.1007/978-94-009-9027-2_2
[12]	Koopmans, T. (1934). Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den einzelnen Elektronen eines Atoms. Physica, 1(1–6), 104–113. https://doi.org/10.1016/S0031-8914(34)90011-2
[13]	Fukui, K. (1982). The Role of Frontier Orbitals in Chemical Reactions (Nobel Lecture). Angewandte Chemie, 21(11), 801–809. https://doi.org/10.1002/anie.198208013
[14]	Cao, Y. et al. (2021). Characterization of the SARS-CoV-2 E Protein: Sequence, Structure, Viroporin, and Inhibitors. Protein science: a publication of the Protein Society, 30(6), 1114–1130. https://doi.org/10.1002/pro.4075
[15]	Baral, B. et al. (2023). SARS-CoV-2 envelope protein induces necroptosis and mediates inflammatory response in lung and colon cells through receptor interacting protein kinase 1. Apoptosis: an international journal on programmed cell death, 28(11-12), 1596–1617. https://doi.org/10.1007/s10495-023-01883-9
[16]	De Maio, F. et al. (2020). Improved binding of SARS-CoV-2 Envelope protein to tight junction-associated PALS1 could play a key role in COVID-19 pathogenesis. Microbes and infection, 22(10), 592–597. https://doi.org/10.1016/j.micinf.2020.08.006
[17]	Talla, A. et al. (2023). Persistent serum protein signatures define an inflammatory subcategory of long COVID. Nat Commun. 14, 3417 https://doi.org/10.1038/s41467-023-38682-4

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APA Style

Santiago-Jiménez, J. C., Ramirez-Damaso, G., Garcia-Quiroz, A., Francisco-Caballero, Castillo-Alvarado, F. D. L. (2025). Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis. Journal of Drug Design and Medicinal Chemistry, 11(4), 63-68. https://doi.org/10.11648/j.jddmc.20251104.12

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ACS Style

Santiago-Jiménez, J. C.; Ramirez-Damaso, G.; Garcia-Quiroz, A.; Francisco-Caballero; Castillo-Alvarado, F. D. L. Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis. J. Drug Des. Med. Chem. 2025, 11(4), 63-68. doi: 10.11648/j.jddmc.20251104.12

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AMA Style

Santiago-Jiménez JC, Ramirez-Damaso G, Garcia-Quiroz A, Francisco-Caballero, Castillo-Alvarado FDL. Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis. J Drug Des Med Chem. 2025;11(4):63-68. doi: 10.11648/j.jddmc.20251104.12

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@article{10.11648/j.jddmc.20251104.12,
  author = {Juan Carlos Santiago-Jiménez and Gabriel Ramirez-Damaso and Alberto Garcia-Quiroz and Francisco-Caballero and Fray de Landa Castillo-Alvarado},
  title = {Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis},
  journal = {Journal of Drug Design and Medicinal Chemistry},
  volume = {11},
  number = {4},
  pages = {63-68},
  doi = {10.11648/j.jddmc.20251104.12},
  url = {https://doi.org/10.11648/j.jddmc.20251104.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jddmc.20251104.12},
  abstract = {Long COVID, or post-COVID-19, is emerging as a prevalent and complex syndrome affecting a significant percentage of patients who have recovered from the acute phase of SARS-CoV-2 infection. The viral envelope protein (E), a 75 amino acid ion channel, is a crucial structural component involved in viral pathogenesis. This study employs density functional theory (DFT) principles to calculate global reactivity descriptors of the short hydrophilic N-terminal domain of the E protein. The results indicate an ionization potential (IP) of 6.47eV, an electron affinity (EA) of 4.39eV, and a molecular hardness (η) of 1.04eV, suggesting moderate to high chemical reactivity. An electrophilicity (ω) value of 14.17eV reveals a marked tendency to accept electrons. These electronic descriptors, along with the described biological functions of the E protein, such as its role in viral assembly, budding, and modulation of the host inflammatory response, position it as a promising therapeutic target. We also report on the reactivity sites (HOMO-LUMO) present in the short hydrophilic N-terminal domain. Inhibition of the E protein could alter key viral processes and attenuate the immune dysregulation underlying persistent COVID-19, opening new avenues for rational drug design.},
 year = {2025}
}

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TY  - JOUR
T1  - Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis
AU  - Juan Carlos Santiago-Jiménez
AU  - Gabriel Ramirez-Damaso
AU  - Alberto Garcia-Quiroz
AU  - Francisco-Caballero
AU  - Fray de Landa Castillo-Alvarado
Y1  - 2025/12/29
PY  - 2025
N1  - https://doi.org/10.11648/j.jddmc.20251104.12
DO  - 10.11648/j.jddmc.20251104.12
T2  - Journal of Drug Design and Medicinal Chemistry
JF  - Journal of Drug Design and Medicinal Chemistry
JO  - Journal of Drug Design and Medicinal Chemistry
SP  - 63
EP  - 68
PB  - Science Publishing Group
SN  - 2472-3576
UR  - https://doi.org/10.11648/j.jddmc.20251104.12
AB  - Long COVID, or post-COVID-19, is emerging as a prevalent and complex syndrome affecting a significant percentage of patients who have recovered from the acute phase of SARS-CoV-2 infection. The viral envelope protein (E), a 75 amino acid ion channel, is a crucial structural component involved in viral pathogenesis. This study employs density functional theory (DFT) principles to calculate global reactivity descriptors of the short hydrophilic N-terminal domain of the E protein. The results indicate an ionization potential (IP) of 6.47eV, an electron affinity (EA) of 4.39eV, and a molecular hardness (η) of 1.04eV, suggesting moderate to high chemical reactivity. An electrophilicity (ω) value of 14.17eV reveals a marked tendency to accept electrons. These electronic descriptors, along with the described biological functions of the E protein, such as its role in viral assembly, budding, and modulation of the host inflammatory response, position it as a promising therapeutic target. We also report on the reactivity sites (HOMO-LUMO) present in the short hydrophilic N-terminal domain. Inhibition of the E protein could alter key viral processes and attenuate the immune dysregulation underlying persistent COVID-19, opening new avenues for rational drug design.
VL  - 11
IS  - 4
ER  -

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Author Information

Juan Carlos Santiago-Jiménez

Department of Experimental Sciences, Institute of Agribusiness Management and Innovation, Mexico;Escuela Superior de Fisicay Matematicas, Instituto Politecnico Nacional, Mexico

Contact Email

http://orcid.org/0000-0002-5394-3884
Gabriel Ramirez-Damaso

Escuela Superior de Fisicay Matematicas, Instituto Politecnico Nacional, Mexico

http://orcid.org/0000-0003-3834-8566
Alberto Garcia-Quiroz

Department of Physics, Autonomous University of Mexico City, Mexico

http://orcid.org/0000-0003-3785-8927
Francisco-Caballero

Department of Chemical Engineering-FESZ-UNAM, National Autonomous University of Mexico, Mexico

http://orcid.org/0000-0002-8483-9924
Fray de Landa Castillo-Alvarado

Escuela Superior de Fisicay Matematicas, Instituto Politecnico Nacional, Mexico

http://orcid.org/0000-0002-2464-8704

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Plain Text BibTeX RIS

APA Style

Santiago-Jiménez, J. C., Ramirez-Damaso, G., Garcia-Quiroz, A., Francisco-Caballero, Castillo-Alvarado, F. D. L. (2025). Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis. Journal of Drug Design and Medicinal Chemistry, 11(4), 63-68. https://doi.org/10.11648/j.jddmc.20251104.12

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ACS Style

Santiago-Jiménez, J. C.; Ramirez-Damaso, G.; Garcia-Quiroz, A.; Francisco-Caballero; Castillo-Alvarado, F. D. L. Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis. J. Drug Des. Med. Chem. 2025, 11(4), 63-68. doi: 10.11648/j.jddmc.20251104.12

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AMA Style

Santiago-Jiménez JC, Ramirez-Damaso G, Garcia-Quiroz A, Francisco-Caballero, Castillo-Alvarado FDL. Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis. J Drug Des Med Chem. 2025;11(4):63-68. doi: 10.11648/j.jddmc.20251104.12

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@article{10.11648/j.jddmc.20251104.12,
  author = {Juan Carlos Santiago-Jiménez and Gabriel Ramirez-Damaso and Alberto Garcia-Quiroz and Francisco-Caballero and Fray de Landa Castillo-Alvarado},
  title = {Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis},
  journal = {Journal of Drug Design and Medicinal Chemistry},
  volume = {11},
  number = {4},
  pages = {63-68},
  doi = {10.11648/j.jddmc.20251104.12},
  url = {https://doi.org/10.11648/j.jddmc.20251104.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jddmc.20251104.12},
  abstract = {Long COVID, or post-COVID-19, is emerging as a prevalent and complex syndrome affecting a significant percentage of patients who have recovered from the acute phase of SARS-CoV-2 infection. The viral envelope protein (E), a 75 amino acid ion channel, is a crucial structural component involved in viral pathogenesis. This study employs density functional theory (DFT) principles to calculate global reactivity descriptors of the short hydrophilic N-terminal domain of the E protein. The results indicate an ionization potential (IP) of 6.47eV, an electron affinity (EA) of 4.39eV, and a molecular hardness (η) of 1.04eV, suggesting moderate to high chemical reactivity. An electrophilicity (ω) value of 14.17eV reveals a marked tendency to accept electrons. These electronic descriptors, along with the described biological functions of the E protein, such as its role in viral assembly, budding, and modulation of the host inflammatory response, position it as a promising therapeutic target. We also report on the reactivity sites (HOMO-LUMO) present in the short hydrophilic N-terminal domain. Inhibition of the E protein could alter key viral processes and attenuate the immune dysregulation underlying persistent COVID-19, opening new avenues for rational drug design.},
 year = {2025}
}

Copy | Download

TY  - JOUR
T1  - Long COVID-19: Electronic Characterization of the SARS-CoV-2 Envelope Protein Using DFT as a Basis for Therapeutic Hypothesis
AU  - Juan Carlos Santiago-Jiménez
AU  - Gabriel Ramirez-Damaso
AU  - Alberto Garcia-Quiroz
AU  - Francisco-Caballero
AU  - Fray de Landa Castillo-Alvarado
Y1  - 2025/12/29
PY  - 2025
N1  - https://doi.org/10.11648/j.jddmc.20251104.12
DO  - 10.11648/j.jddmc.20251104.12
T2  - Journal of Drug Design and Medicinal Chemistry
JF  - Journal of Drug Design and Medicinal Chemistry
JO  - Journal of Drug Design and Medicinal Chemistry
SP  - 63
EP  - 68
PB  - Science Publishing Group
SN  - 2472-3576
UR  - https://doi.org/10.11648/j.jddmc.20251104.12
AB  - Long COVID, or post-COVID-19, is emerging as a prevalent and complex syndrome affecting a significant percentage of patients who have recovered from the acute phase of SARS-CoV-2 infection. The viral envelope protein (E), a 75 amino acid ion channel, is a crucial structural component involved in viral pathogenesis. This study employs density functional theory (DFT) principles to calculate global reactivity descriptors of the short hydrophilic N-terminal domain of the E protein. The results indicate an ionization potential (IP) of 6.47eV, an electron affinity (EA) of 4.39eV, and a molecular hardness (η) of 1.04eV, suggesting moderate to high chemical reactivity. An electrophilicity (ω) value of 14.17eV reveals a marked tendency to accept electrons. These electronic descriptors, along with the described biological functions of the E protein, such as its role in viral assembly, budding, and modulation of the host inflammatory response, position it as a promising therapeutic target. We also report on the reactivity sites (HOMO-LUMO) present in the short hydrophilic N-terminal domain. Inhibition of the E protein could alter key viral processes and attenuate the immune dysregulation underlying persistent COVID-19, opening new avenues for rational drug design.
VL  - 11
IS  - 4
ER  -

Copy | Download