The Efficiency of High-Throughput Screening (HTS) and in-silico data analysis during medical emergencies: identification of effective antiviral 3CLpro inhibitors.

Antiviral Research, Journal Year: 2025, Volume and Issue: unknown, P. 106119 - 106119

Published: Feb. 1, 2025

Language: Английский

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Biochemical Screening of Phytochemicals and Identification of Scopoletin as a Potential Inhibitor of SARS-CoV-2 Mpro, Revealing Its Biophysical Impact on Structural Stability

Viruses, Journal Year: 2025, Volume and Issue: 17(3), P. 402 - 402

Published: March 12, 2025

The main protease (Mpro or 3CLpro nsp5) of SARS-CoV-2 is crucial to the life cycle and pathogenesis SARS-CoV-2, making it an attractive drug target develop antivirals. This study employed virtual screening a few phytochemicals, resultant best compound, Scopoletin, was further investigated by FRET-based enzymatic assay, revealing experimental IC50 15.75 µM. impact Scopoletin on Mpro biophysical MD simulation studies. Fluorescence spectroscopy identified strong binding constant 3.17 × 104 M⁻1 for Mpro, as demonstrated its effective fluorescence quenching Mpro. Additionally, CD showed significant reduction in helical content upon interaction with Scopoletin. findings thermodynamic measurements using isothermal titration calorimetry (ITC) supported spectroscopic data, indicating tight KA 2.36 103 M−1. Similarly, studies have also revealed that forms hydrogen bonds amino acids nearest active site, this has been molecular dynamics These indicate may be developed potential antiviral treatment targeting

Language: Английский

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In Silico and In Vitro Studies of the Approved Antibiotic Ceftaroline Fosamil and Its Metabolites as Inhibitors of SARS-CoV-2 Replication

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 491 - 491

Published: March 28, 2025

The SARS-CoV-2 proteases Mpro and PLpro are critical targets for antiviral drug development the treatment of COVID-19. 1,2,4-thiadiazole functional group is an inhibitor cysteine proteases, such as papain cathepsins. This chemical moiety also present in ceftaroline fosamil (CF), FDA-approved fifth-generation cephalosporin antibiotic. study investigates interactions between CF, its primary metabolites (M1 dephosphorylated CF M2 opened β-lactam ring) derivatives (protonated M1H M2H), open rings (open-M1H open-M2H) with evaluates CF’s effects on vitro viral replication. In silico analyses (molecular docking molecular dynamics (MD) simulations) demonstrated that potential inhibitors Mpro. Docking analysis indicated majority ligands were more stable than PLpro; however, biochemical preferred target CF. inhibited replication human Calu-3 cell model at submicromolar concentrations when added to culture medium 12 h. Our results suggest should be evaluated a repurposing agent COVID-19, considering not only but other relevant cellular pathways. Additionally, reactivity sulfur warrants further exploration protease inhibitors.

Language: Английский

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Investigation of the Interaction Between 4‐Thiazolidinone Derivatives and SARS‐CoV‐2 Mpro Using Spectroscopy and Microscale Thermophoresis

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(15)

Published: April 1, 2025

Abstract Since the outbreak of COVID‐19, one strategies used to search for potential drugs has been screen inhibitors SARS‐CoV‐2 Mpro. This work investigated inhibitory effects 4‐thiazolidinone derivatives on main protease (Mpro) using various methods, including enzyme activity assays, kinetics, spectroscopy experiments, molecular docking simulations, microscale thermophoresis, and cytotoxicity tests. Compound 3a demonstrated best inhibition effect among compounds tested, with IC 50 = 2.36 ± 0.36 µM K i 1.72 µM. The trifluoromethyl group in might enhance its ability. Interactions between Mpro resulted fluorescence quenching primarily through static quenching. Thermodynamic analysis indicated that interaction forces are mainly hydrogen bonds van der Waals forces. Spectral results revealed affected microenvironment aromatic amino acid residues altered secondary structure. Differential scanning fluorimetry was confirm Results thermophoresis d 1.56 0.24 Molecular simulations provided a more intuitive visualization study provides clues screening novel inhibitors.

Language: Английский

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Structural-based virtual screening of Ebselen derivatives to identify potential SARS-CoV-2 main protease inhibitors, utilizing 3D-QSAR models, molecular docking, MD simulation, and quantum mechanical calculations

Network Modeling Analysis in Health Informatics and Bioinformatics, Journal Year: 2025, Volume and Issue: 14(1)

Published: May 19, 2025

Language: Английский

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Drug repurposing targeting COVID-19 3CL protease using molecular docking and machine learning regression approaches

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: May 28, 2025

The COVID-19 pandemic has initiated a global health emergency, with an exigent need for effective cure. Progressively, drug repurposing is emerging as promising solution saving time, cost, and labor. However, the number of candidates that have been identified treatment still insufficient, so more thorough exploration strategies are required. In this study, we joined molecular docking machine learning approaches to find some prospective therapeutic treatment. We screened 5903 approved drugs their inhibition by targeting replicating enzyme 3CLpro SARS-CoV-2. Molecular used calculate binding affinities these towards 3CLpro. employed several QSAR modeling explore potential high affinities. Our outcomes demonstrated Decision Tree Regression (DTR) model, best scores R² RMSE, most suitable model drugs. shortlisted six favorable respective Zinc IDs (3873365, 85432544, 203757351, 85536956, 8214470, 261494640) within range -15 kcal/mol -13 kcal/mol. further examined physiochemical pharmacokinetic properties potent study provides efficient framework against establishes impending combination accelerate identification candidates. verdicts contribute larger goal finding cures COVID-19, which acute challenge. our provide valuable insights into

Language: Английский

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Advances in the Search for SARS-CoV-2 Mpro and PLpro Inhibitors

Pathogens, Journal Year: 2024, Volume and Issue: 13(10), P. 825 - 825

Published: Sept. 24, 2024

SARS-CoV-2 is a spherical, positive-sense, single-stranded RNA virus with large genome, responsible for encoding both structural proteins, vital the viral particle’s architecture, and non-structural critical virus’s replication cycle. Among two cysteine proteases emerge as promising molecular targets design of new antiviral compounds. The main protease (Mpro) homodimeric enzyme that plays pivotal role in formation replication–transcription complex, associated papain-like (PLpro), modulates host immune signaling by reversing post-translational modifications ubiquitin interferon-stimulated gene 15 (ISG15) cells. Due to importance these development novel anti-SARS-CoV-2 drugs, purpose this review address aspects related structure, mechanism action strategies inhibitors capable targeting Mpro PLpro. Examples covalent non-covalent are currently being evaluated preclinical clinical studies or already approved therapy will be also discussed show advances medicinal chemistry search molecules treat COVID-19.

Language: Английский

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Marine Origin vs. Synthesized Compounds: In Silico Screening for a Potential Drug Against SARS-CoV-2

Scientia Pharmaceutica, Journal Year: 2024, Volume and Issue: 93(1), P. 2 - 2

Published: Dec. 26, 2024

Although COVID-19 is not a pandemic anymore, the virus frequently mutates, resulting in new strains and presenting global public health challenges. The lack of oral antiviral drugs makes it difficult to treat him, which creation broadly acting antivirals necessary fight current next epidemics viruses. Using molecular docking approach, 118 compounds derived from marine organisms 92 previously synthesized were screened assess their binding affinity for main protease papain-like enzymes SARS-CoV-2. best candidates xanthene, benzoxazole, coumarin classes identified. Marine-derived showed slightly better potential as enzyme inhibitors, though affinities similar, with displaying values between 0.2 0.4 mM. Xanthenes, among both origin compounds, emerged most promising scaffolds further research inhibitors. was found be more druggable than protease. Additionally, all top met criteria various drug-likeness properties, indicating good bioavailability low risk adverse effects. This provides valuable insights into comparative coumarin, benzoxazole classes, highlighting vitro vivo studies.

Language: Английский

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Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M^pro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19623 - 19667

Published: Oct. 25, 2024

The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. main protease (M

Language: Английский

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Synthesis, characterization, proteolytic activity inhibition, ADMET prediction, and molecular docking studies of novel indole derivatives as potential SARS-CoV-2 protease inhibitors

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1323, P. 140707 - 140707

Published: Nov. 10, 2024

Language: Английский

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