Applications of Machine Learning Approaches for the Discovery of SARS-CoV-2 PLpro Inhibitors

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

The global impact of SARS-CoV-2 highlights the need for treatments beyond vaccination, given limited availability effective medications. While Pfizer introduced Paxlovid, an FDA-approved antiviral targeting main protease (Mpro), this study focuses on designing new antivirals against another protease, papain-like (PLpro), which is crucial viral replication and immune suppression. NCATS/NIH performed a high-throughput screen ∼15,000 molecules from internal molecular library, identifying initial hits with 0.5% success rate. To improve hit rate identify potent inhibitors, machine learning-based virtual screens were applied to ∼150,000 compounds, yielding 125 top predicted hits. Biochemical evaluation revealed 25 promising 20% hit-rate IC50 values 1.75 μM <36 across 13 chemotypes. Further analog screening those chemotypes, as part structure–activity relationships, led 20 additional Additionally, hit-to-lead optimization chemotype 7 produced 10 more analogs. These PLpro inhibitors provide templates development COVID-19.

Language: Английский

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Preclinical and Clinical Investigations of Potential Drugs and Vaccines for COVID-19 Therapy: A Comprehensive Review With Recent Update

Clinical Pathology, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 1, 2024

The COVID-19 pandemic-led worldwide healthcare crisis necessitates prompt societal, ecological, and medical efforts to stop or reduce the rising number of fatalities. Numerous mRNA based vaccines for viral vectors have been licensed use in emergencies which showed 90% 95% efficacy preventing SARS-CoV-2 infection. However, safety issues, vaccine reluctance, skepticism remain major concerns making mass vaccination a successful approach treat COVID-19. Hence, alternative therapeutics is needed eradicating global burden from developed low-resource countries. Repurposing current medications drug candidates could be more viable option treating as these therapies previously passed significant checkpoints development patient care. Besides vaccines, this review focused on potential usage therapeutic agents including antiviral, antiparasitic, antibacterial drugs, protease inhibitors, neuraminidase monoclonal antibodies that are currently undergoing preclinical clinical investigations assess their effectiveness treatment Among repurposed remdesivir considered most promising agent, while favipiravir, molnupiravir, paxlovid, lopinavir/ritonavir exhibited improved effects terms elimination viruses. outcomes with oseltamivir, umifenovir, disulfiram, teicoplanin, ivermectin were not significant. It noteworthy combining multiple drugs therapy showcases impressive managing individuals Tocilizumab presently employed patients who exhibit COVID-19-related pneumonia. antiviral such galidesivir, griffithsin, thapsigargin under trials severe symptoms. Supportive may involve corticosteroids, convalescent plasma, stem cells, pooled antibodies, vitamins, natural substances. This study provides an updated progress crucial guide inventing novel interventions against

Language: Английский

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Covalent small-molecule inhibitors of SARS-CoV-2 Mpro: Insights into their design, classification, biological activity, and binding interactions

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116704 - 116704

Published: Aug. 8, 2024

Language: Английский

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Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

RSC Advances, Journal Year: 2023, Volume and Issue: 13(50), P. 35500 - 35524

Published: Jan. 1, 2023

The pandemic caused by the coronavirus SARS-CoV-2 led to a global crisis in world healthcare system. Despite some progress creation of antiviral vaccines and mass vaccination population, number patients continues grow because spread new mutations. There is an urgent need for direct-acting drugs capable suppressing or stopping main mechanisms reproduction SARS-CoV-2. Several studies have shown that successful replication virus cell requires proteolytic cleavage protein structures virus. Two proteases are crucial replicating other coronaviruses: protease (Mpro) papain-like (PLpro). In this review, we summarize essential viral proteins required its life cycle as targets chemotherapy infection provide critical summary development against COVID-19 from drug repurposing strategy up molecular design novel covalent non-covalent agents inhibiting replication. We overview choice Mpro PLpro promising pharmacological impact on cycle.

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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In Silico and In Vitro Studies of Terpenes from the Fabaceae Family Using the Phenotypic Screening Model against the SARS-CoV-2 Virus

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(7), P. 912 - 912

Published: July 9, 2024

In 2019, the emergence of seventh known coronavirus to cause severe illness in humans triggered a global effort towards development new drugs and vaccines for SARS-CoV-2 virus. These efforts are still ongoing 2024, including present work where we conducted ligand-based virtual screening terpenes with potential anti-SARS-CoV-2 activity. We constructed Quantitative Structure–Activity Relationship (QSAR) model from compounds activity against accuracy 0.71. utilized this predict series 217 isolated Fabaceae family. Four compounds, predominantly triterpenoids lupane series, were subjected an vitro phenotypic Vero CCL-81 cells assess their inhibitory SARS-CoV-2. The which showed high rates inhibition along substantial cell viability underwent molecular docking at main protease, papain-like spike protein RNA-dependent RNA polymerase. Overall, through our QSAR successfully identified highest probability activity, as validated using study. This confirms promising candidates therapeutics.

Language: Английский

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Learning from COVID-19: How drug hunters can prepare for the next pandemic

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(10), P. 103723 - 103723

Published: July 22, 2023

Language: Английский

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A phenothiazine urea derivative broadly inhibits coronavirus replication via viral protease inhibition

Antiviral Research, Journal Year: 2023, Volume and Issue: 220, P. 105758 - 105758

Published: Nov. 24, 2023

Language: Английский

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Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 12, 2023

ABSTRACT Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array non-structural proteins involved in replication, organelle formation, RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two cysteine proteases, main protease (M pro ) papain-like (PL ), that mediate polyprotein cleavage. Using a structure-guided approach, phenothiazine urea derivative inhibits both SARS-CoV-2 M PL activity vitro was identified. In silico docking studies also predicted binding the to active sites from distantly related alphacoronavirus, HCoV-229E (229E) betacoronavirus, HCoV-OC43 (OC43). The lead displayed broad antiviral against all three HCoVs tested cell culture infection models. It further demonstrated compound inhibited 229E OC43 at early stage with diminished formation organelles RNAs are made within them, as expected following inhibition. These observations suggest may broadly inhibit proteases diverse coronaviruses. Graphical Abstract Highlights targets for novel agents Phenothiazine ureas Some coronaviruses minimal cytotoxicity stages coronavirus consistent failure

Language: Английский

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Drug-target prediction through self supervised learning with dual task ensemble approach

Computational Biology and Chemistry, Journal Year: 2024, Volume and Issue: 113, P. 108244 - 108244

Published: Oct. 11, 2024

Language: Английский

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