Insights from a computational analysis of the SARS‐CoV‐2 Omicron variant: Host–pathogen interaction, pathogenicity, and possible drug therapeutics
Md Sorwer Alam Parvez, Manash Kumar Saha, Md D Ibrahim, Yusha Araf, Md. Taufiqul Islam, Gen Ohtsuki, Mohammad Jakir Hosen
Immunity, Inflammation and Disease, doi:10.1002/iid3.639
Introduction: Prominently accountable for the upsurge of COVID-19 cases as the world attempts to recover from the previous two waves, Omicron has further threatened the conventional therapeutic approaches. The lack of extensive research regarding Omicron has raised the need to establish correlations to understand this variant by structural comparisons. Here, we evaluate, correlate, and compare its genomic sequences through an immunoinformatic approach to understand its epidemiological characteristics and responses to existing drugs.
Methods: We reconstructed the phylogenetic tree and compared the mutational spectrum. We analyzed the mutations that occurred in the Omicron variant and correlated how these mutations affect infectivity and pathogenicity. Then, we studied how mutations in the receptor-binding domain affect its interaction with host factors through molecular docking. Finally, we evaluated the drug efficacy against the main protease of the Omicron through molecular docking and validated the docking results with molecular dynamics simulation. Results: Phylogenetic and mutational analysis revealed the Omicron variant is similar to the highly infectious B.1.620 variant, while mutations within the prominent proteins are hypothesized to alter its pathogenicity. Moreover, docking evaluations revealed significant differences in binding affinity with human receptors, angiotensin-converting enzyme 2 and NRP1. Surprisingly, most of the tested drugs were proven to be effective. Nirmatrelvir, 13b, and Lopinavir displayed increased effectiveness against Omicron. Conclusion: Omicron variant may be originated from the highly infectious B.1.620 variant, while it was less pathogenic due to the mutations in the prominent proteins. Nirmatrelvir, 13b, and Lopinavir would be the most effective, compared to other promising drugs that were proven effective.
AUTHOR CONTRIBUTIONS Md Sorwer Alam Parvez: Conceptualization; methodology; formal analysis; data interpretation; validation; visualization; original draft preparation. Manash Kumar Saha: Methodology; software; visualization. Md Ibrahim: Formal analysis. Yusha Araf: Formal analysis; original draft preparation and editing. Md Taufiqul Islam: Validation. Gen Ohtsuki: Supervision, writing-review & editing. Mohammad Jakir Hosen: Supervision, writing-review & editing.
ACKNOWLEDGMENT This study was supported by grants from the Mitsubishi Foundation, the Takeda Science Foundation (to G. O.).
CONFLICTS OF INTEREST The authors declare no conflicts of interest.
ETHICS STATEMENT This study did not deal with human subjects and biological materials. All open-source data were analyzed, in which all personal information was anonymized, and no data allowing individual identification was retained. Therefore, no ethics approval and no informed consent were required.
References
Abascal, Vega, A general purpose model for the condensed phases of water: TIP4P/2005, J Chem Phys
Abraham, Murtola, Schulz, GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX
Angelini, Akhlaghpour, Neuman, Buchmeier, Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles, mBio,
doi:10.1128/mBio.00524-13Barton, Macgowan, Kutuzov, Dushek, Barton et al., Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics, eLife
Behzadi, Gajdács, Writing a strong scientific paper in medicine and the biomedical sciences: a checklist and recommendations for early career researchers, Biol Futur,
doi:10.1007/s42977-021-00095-zBenvenuto, Angeletti, Giovanetti, Evolutionary analysis of SARS-CoV-2: how mutation of non-structural protein 6 (NSP6) could affect viral autophagy, J Infect,
doi:10.1016/j.jinf.2020.03.058Biovia, Systèmes, BIOVIA Discovery studio
Collie, Champion, Moultrie, Bekker, Gray, Effectiveness of BNT162b2 vaccine against omicron variant in South Africa, N Engl J Med,
doi:10.1056/NEJMc2119270Colovos, Yeates, Verification of protein structures: patterns of nonbonded atomic interactions, Prot Sci,
doi:10.1002/pro.5560020916Cong, Ulasli, Schepers, Nucleocapsid protein recruitment to replication-transcription complexes plays a crucial role in coronaviral life cycle, J Virol,
doi:10.1128/jvi.01925-19Delano, The PyMOL molecular graphics system
Dolinsky, Nielsen, Mccammon, Baker, PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations, Nucleic Acids Res,
doi:10.1093/nar/gkh381Dudas, Hong, Potter, Emergence and spread of SARS-CoV-2 lineage B. 1.620 with variant of concern-like mutations and deletions, Nat Commun,
doi:10.1038/s41467-021-26055-8Edgar, MUSCLE: multiple sequence alignment with high accuracy and high throughput, Nucleic Acids Res,
doi:10.1093/nar/gkh340Essahib, Verheyen, Tournaye, Van De Velde, SARS-CoV-2 host receptors ACE2 and CD147 (BSG) are present on human oocytes and blastocysts, J Assist Reprod Genet,
doi:10.1007/s10815-020-01952-xFleming, Shubin, Sussman, Casteel, Stohlman, Monoclonal antibodies to the matrix (El) glycoprotein of mouse hepatitis virus protect mice from encephalitis, Virology,
doi:10.1016/0042-6822(89)90415-7Gorkhali, Koirala, Rijal, Mainali, Baral et al., Structure and function of major SARS-CoV-2 and SARS-CoV proteins, Bioinform Biol Insights,
doi:10.1177/11779322211025876Gu, Krishnan, Ng, Probable transmission of SARS-CoV-2 Omicron variant in quarantine hotel, Hong Kong, China, November 2021, Emerging Infect Dis
Hoang, Chernomor, Haeseler, Minh, Vinh, UFBoot2: improving the ultrafast bootstrap approximation, Mol Biol Evol,
doi:10.1093/molbev/msx281Hoffmann, Krüger, Schulz, The Omicron variant is highly resistant against antibody-mediated neutralization: implications for control of the COVID-19 pandemic, Cell,
doi:10.1016/j.cell.2021.12.032Jassat, Karim, Mudara, Clinical severity of covid-19 patients admitted to hospitals in Gauteng, South Africa during the Omicron-dominant fourth wave, Preprints with the Lancet,
doi:10.2139/ssrn.3996320Kalyaanamoorthy, Minh, Wong, Haeseler, Jermiin, ModelFinder: fast model selection for accurate phylogenetic estimates, Nat Methods,
doi:10.1038/nmeth.4285Kannan, Spratt, Cohen, Evolutionary analysis of the Delta and Delta Plus variants of the SARS-CoV-2 viruses, J Autoimmun,
doi:10.1016/j.jaut.2021.102715Kannan, Spratt, Sharma, Chand, Byrareddy et al., Omicron SARS-CoV-2 variant: unique features and their impact on pre-existing antibodies, J Autoimmun,
doi:10.1016/j.jaut.2021.102779Kiefer, Arnold, Künzli, Bordoli, Schwede, The SWISS-MODEL Repository and associated resources, Nucleic Acids Res,
doi:10.1093/nar/gkn750Kumar, Stecher, Li, Knyaz, Tamura, MEGA X: molecular evolutionary genetics analysis across computing platforms, Mol Biol Evol,
doi:10.1093/molbev/msy096Kumari, Kumar, Open Source Drug Discovery Consortium, Lynn A. g_mmpbsa: a GROMACS tool for highthroughput MM-PBSA calculations, J Chem Inf Model
Laskowski, Macarthur, Moss, Thornton, PROCHECK: a program to check the stereochemical quality of protein structures, J Appl Crystal,
doi:10.1107/S0021889892009944Letunic, Bork, Interactive Tree Of Life (iTOL): an online tool for phylogenetic tree display and annotation, Bioinformatics,
doi:10.1093/nar/gkab301Li, Wang, Lavrijsen, SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination, Cell Res,
doi:10.1038/s41422-022-00618-wLuo, Liu, Wang, Gong, From SARS to the Omicron variant of COVID-19: China's policy adjustments and changes to prevent and control infectious diseases, Biosci Trends,
doi:10.5582/bst.2021.01535Minh, Schmidt, Chernomor, IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era, Mol Biol Evol,
doi:10.1093/molbev/msaa015Nelson, Stohlman, Tahara, High affinity interaction between nucleocapsid protein and leader/intergenic sequence of mouse hepatitis virus RNA, Microbiology,
doi:10.1099/0022-1317-81-1-181Poudel, Ishak, Perez-Fernandez, Highly mutated SARS-CoV-2 Omicron variant sparks significant concern among global experts-what is known so far?, Travel Med Infect Dis,
doi:10.1016/j.tmaid.2021.102234Torjesen, Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear, BMJ,
doi:10.1136/bmj.n2943Trott, Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J Comput Chem,
doi:10.1002/jcc.21334Van Gunsteren, Billeter, Eising, Biomolecular simulation: the GROMOS96 manual and user guide. Vdf Hochschulverlag AG an der ETH Zürich
Vandyck, Deval, Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection, Curr Opin Virol,
doi:10.1016/j.coviro.2021.04.006Vangeel, Chiu, Jonghe, Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host-pathogen interaction, pathogenicity, and possible drug therapeutics, Immun Inflamm Dis
Vanommeslaeghe, Hatcher, Acharya, CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields, J Comput Chem,
doi:10.1002/jcc.21367Vita, Chini, Bifulco, Lauro, Insights into the ligand binding to bromodomain-containing protein 9 (BRD9): a guide to the selection of potential binders by computational methods, Molecules
Wishart, Feunang, Guo, DrugBank 5.0: a major update to the DrugBank database for 2018, Nucleic Acids Res,
doi:10.1093/nar/gkx1037Zhang, Lin, Sun, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science,
doi:10.1126/science.abb3405Zhu, Lee, Van De Leemput, Lee, Han, Functional analysis of SARS-CoV-2 proteins in Drosophila identifies Orf6-induced pathogenic effects with Selinexor as an effective treatment, Cell Biosci,
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'ISSN': ['2050-4527', '2050-4527'],
'subject': ['Immunology', 'Immunology and Allergy'],
'container-title-short': 'Immunity Inflam & Disease',
'published': {'date-parts': [[2022, 6, 21]]},
'assertion': [ { 'value': '2022-02-08',
'order': 0,
'name': 'received',
'label': 'Received',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2022-04-20',
'order': 1,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2022-06-21',
'order': 2,
'name': 'published',
'label': 'Published',
'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
