SARS-CoV-2 Omicron Subvariants Do Not Differ Much in Binding Affinity to Human ACE2: A Molecular Dynamics Study

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(14), P. 3340 - 3349

Published: April 2, 2024

The emergence of the variant concern Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exacerbates COVID-19 pandemic due to its high contagious ability. Studies have shown that binds human ACE2 more strongly than wild type. prevalence in new cases promotes novel lineages with improved receptor binding affinity and immune evasion. To shed light on this open problem, work, we investigated free energy domain BA.2, BA.2.3.20, BA.3, BA4/BA5, BA.2.75, BA.2.75.2, BA.4.6, XBB.1, XBB.1.5, BJ.1, BN.1, BQ.1.1, CH.1.1 using all-atom molecular dynamics simulation mechanics Poisson–Boltzmann surface area method. results show these increased compared BA.1 lineage, BA.2.75 BA.2.75.2 subvariants bind others. However, general, affinities do not differ significantly from each other. electrostatic force dominates over van der Waals interaction between cells. Based our results, argue viral evolution does further improve SARS-CoV-2 for but may increase

Language: Английский

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Exploring the natural products chemical space to abrogate the F3L-dsRNA interface of monkeypox virus to enhance the immune responses using molecular screening and free energy calculations

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 10, 2024

Amid the ongoing monkeypox outbreak, there is an urgent need for rapid development of effective therapeutic interventions capable countering immune evasion mechanisms employed by virus (MPXV). The strategy involves binding F3L protein to dsRNA, resulting in diminished interferon (IFN) production. Consequently, our current research focuses on utilizing virtual drug screening techniques target RNA domain protein. Out 954 compounds within South African natural compound database, only four demonstrated notable docking scores: −6.55, −6.47, −6.37, and −6.35 kcal/mol. dissociation constant (KD) analysis revealed a stronger affinity top hits 1-4 (−5.34, −5.32, −5.29, −5.36 kcal/mol) with MPXV. All-atom simulations top-ranked 1 4 consistently exhibited stable dynamics, suggesting their potential interact effectively interface residues. This was further substantiated through analyses parameters such as radius gyration (Rg), Root Mean Square Fluctuation, hydrogen bonding. Cumulative assessments free energy confirmed top-performing candidates among all compounds, values −35.90, −52.74, −28.17, −32.11 kcal/mol 1-4, respectively. These results indicate that hit could hold significant promise advancing innovative therapies, suitability both vivo vitro experiments.

Language: Английский

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Understanding the Effectiveness of the Comirnaty Monovalent and Bivalent Vaccines During the Winter Coronavirus (COVID-19) Infection Survey

Journal of Infection, Journal Year: 2025, Volume and Issue: unknown, P. 106461 - 106461

Published: March 1, 2025

Highlights•The Comirnaty Omicron XBB.1.5 vaccine demonstrated moderate short-term protection against infection and symptomatic infection, reaching peak effectiveness between 2 to 5 weeks post-vaccination.•Approximately 9 12 after vaccination, the protective effect of booster declined near zero both infection.•The BA.5 bivalent showed no evidence within study period, with estimates wide confidence intervals indicating considerable uncertainty.•These findings emphasize need for adaptive strategies development variant-targeted vaccines maintain emerging SARS-CoV-2 variants.AbstractBackgroundUnderstanding over time is critical informing strategies, types, public health policies, particularly continued emergence novel variants.MethodsThe Winter Coronavirus (COVID-19) Infection Study (WCIS), conducted from November 2023 March 2024, involved approximately 150,000 participants aged 3 years older England Scotland. The WCIS tested at regular using lateral flow tests estimate prevalence incidence in real-time. Survival analysis Cox proportional hazards regression was conducted, data linked participant vaccination records, evaluate association since risk infection. Vaccine (VE) evaluated those 65 old over. model incorporated time-varying covariates counting process framework, stratified baseline by age group, region, time, included key such as sex, clinical status, ethnicity, socioeconomic indicators. VE estimated hazard ratios, penalised cubic splines were used capture nonlinear effects vaccination.ResultsWe that peaked day 14 post-vaccination, 70.63% (95% Confidence Intervals (CI): 43.33%, 84.78%) 63.62% CI: 22.69%, 82.88%) rapidly 9-12 post point close uncertainty 60 onwards. In contrast, crossing zero.ConclusionsThese provide important insights into targeted context an evolving pandemic. As continues mutate, approaches design policy will be addressing variants protecting high-risk groups.

Language: Английский

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Role of N-linked glycosylation sites in human ACE2 in SARS-CoV-2 and hCoV-NL63 infection

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

ABSTRACT Angiotensin-converting enzyme 2 (ACE2) is a transmembrane protein known for its physiological role in the renin-angiotensin system that also serves as receptor entry of SARS-CoV-1, SARS-CoV-2, and seasonal human coronavirus NL63 (hCoV-NL63). ACE2 contains seven N-linked glycosylation sites. Molecular simulation binding analyses suggest some them are involved interaction with Spike (S) proteins hCoVs, but their relevance S-mediated fusion viral poorly investigated. To address this, we determined impact all sites on SARS-CoV-2 hCoV-NL63 infection well cell-to-cell fusion. We found mutant expressed localized at cell surface, albeit lacks glycans decreased levels. On average, changes T92I, N322A, N690A, combined mutation increased endocytic VSVpp mediated by early HU-1 Omicron BA.2, BA.5, XBB.1.5 S proteins. In comparison, only lack glycan N322 enhanced syncytia formation case Changes N90A, N322A strain about twofold to threefold had lesser effects genuine variants. Despite reduced surface expression ACE2, elimination usually via pathway while having little effect presence TMPRSS2. Our results provide insights into ability (hACE2) serve receptors infection. IMPORTANCE Several coronaviruses use angiotensin-converting primary cells. glycosylated distinct positions, target cells incompletely understood. Here, examined individual mutations hACE2 Spike-mediated VSV-pseudoparticle new information highly pathogenic coronaviruses.

Language: Английский

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Exploring Global Natural Product Databases for NLRP3 Inhibition: Unveiling novel combinatorial therapeutic strategy for Hidradenitis Suppurativa

Journal of Infection and Public Health, Journal Year: 2025, Volume and Issue: 18(4), P. 102697 - 102697

Published: Feb. 14, 2025

Language: Английский

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Medicinal Phytocompounds as Potential Inhibitors of p300-HIF1α Interaction: A Structure-Based Screening and Molecular Dynamics Simulation Study

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(4), P. 602 - 602

Published: April 21, 2025

Background: Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible factor-1 (HIF-1). For HIF-1 to function under low oxygen conditions, it must interact with the transcriptional coactivator p300, critical step for promoting cell survival adaptation hypoxic environments. Methods: Consequently, we used drug design molecular simulation techniques screen phytochemical databases, including traditional Chinese African medicine sources, compounds that could disrupt p300/HIF-1 interaction. Results: In this study, identified potential high docking scores such as EA-176920 (−8.719), EA-46881231 (−8.642), SA-31161 (−9.580), SA-5280863 (−8.179), NE-5280362 (−10.287), NE-72276 (−9.017), NA-11210533 (−10.366), NA-11336960 (−7.818), TCM-5281792 (−12.648), TCM-6441280 (−9.470 kcal/mol) lead compounds. Furthermore, compound highest score from each database (EA-176920, SA-31161, NE-5280362, NA-11210533, TCM-5281792) was subjected further analysis. The stable binding affinity of these p300 confirmed Post-simulation free energy (−22.0020 kcal/mol, −25.4499 −32.4530 −33.9918 −57.7755 respectively) KD Moreover, selected followed Lipinski rules favorable ADMET properties like efficient intestinal absorption, water solubility, no toxicity. Conclusions: Our findings highlight natural target protein–protein interactions lay groundwork future vitro vivo studies explore their therapeutic potential. Specifically, disrupting interaction interfere hypoxia-driven pathways promote tumor growth, angiogenesis, metastasis, offering promising strategy suppress progression at level.

Language: Английский

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Novel Omicron Variants Enhance Anchored Recognition of TMEM106B: A New Pathway for SARS-CoV-2 Cellular Invasion

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(3), P. 671 - 680

Published: Jan. 11, 2024

The recent discovery that TMEM106B serves as a receptor mediating ACE2-independent SARS-CoV-2 entry into cells deserves attention, especially in the background of frequent emergence mutant strains. Here, structure-dynamic features this novel pathway are dissected deeply. Our investigation revealed large loop (RBD@471-491) could anchor TMEM106B, which was then firmly locked by another (RBD@444-451). and widely disseminated Omicron variants (BA.2.86/EG.5.1) affect anchoring recognition proteins, with BA.2.86 being more likely to impact limited or undetectable ACE2 expression. EG.5.1 variant captures poorly due impaired electrostatic complementarity. Furthermore, we emphasize antibody design against these two loops enhance protection low-expressing according alanine scanning mutagenesis multiple antibodies. We hope study will provide perspective for prevention treatment new viral invasion pathway.

Language: Английский

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Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response

Frontiers in Chemistry, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 16, 2024

SARS-CoV-2, also referred to as severe acute respiratory syndrome coronavirus 2, is the virus responsible for causing COVID-19, an infectious disease that emerged in Wuhan, China, December 2019. Among its crucial functions, NSP6 plays a vital role evading human immune system by directly interacting with receptor called TANK-binding kinase (TBK1), leading suppression of IFNβ production. Consequently, present study we used structural and biophysical approaches analyze effect newly mutations on binding TBK1. identified mutations, four (F35G, L37F, L125F, I162T) were found significantly destabilize structure NSP6. Furthermore, molecular docking analysis highlighted mutant displayed highest affinity TBK1, exhibiting scores −1436.2 wildtype −1723.2, −1788.6, −1510.2, −1551.7 F35G, I162T mutants, respectively. This suggests potential enhanced evasion capability Particularly, F35G mutation exhibited strongest affinity, supported calculated free energy −172.19 kcal/mol. To disrupt between conducted virtual drug screening develop novel inhibitor derived from natural products. From this screening, top 5 hit compounds most promising candidates score −6.59 kcal/mol, −6.52 −6.32 −6.22 −6.21 The dynamic simulation 3 hits further verified stability drugs-NSP6 complexes. In conclusion, provides valuable insight into higher infectivity SARS-CoV-2 new variants strong rationale development drugs against

Language: Английский

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Molecular screening of phytocompounds targeting the interface between influenza A NS1 and TRIM25 to enhance host immune responses

Journal of Infection and Public Health, Journal Year: 2024, Volume and Issue: 17(7), P. 102448 - 102448

Published: May 10, 2024

Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza virus's NS1 hinders this process binding TRIM25, disrupting its association with and preventing downstream signalling, contributing evasion of immune response. In our study we used structural-based drug designing, molecular simulation, free energy approaches identify potent phytocompounds from various natural product databases (>100,000 compounds) able inhibit screening identified EA-8411902 EA-19951545 East African Natural Products Database, NA-390261 NA-71 North SA-65230 SA- 4477104 South Compounds NEA- 361 4524784 North-East TCM-4444713 TCM-6056 Traditional Chinese Medicines Database top hits. docking energies results revealed that these compounds have high affinity specific active site residues (Leu95, Ser99, Tyr89) involved interaction Additionally, analysis structural dynamics, energy, dissociation constants demonstrates notably stronger protein. Moreover, all selected exhibit exceptional ADMET properties, including water solubility, gastrointestinal absorption, an absence hepatotoxicity, while adhering Lipinski's rule. Our simulation findings highlight demonstrate NS1-TRIM25 interaction, adhere drug-likeness criteria, thus presenting promising candidates further development antiviral agents against

Language: Английский

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Development of a potent recombinant scFv antibody against the SARS-CoV-2 by in-depth bioinformatics study: Paving the way for vaccine/diagnostics development

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 170, P. 108091 - 108091

Published: Jan. 28, 2024

Language: Английский

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