Docking and Post-Processing of 1 Million Molecules from the CNCL Database in Search of SARS-CoV-2 Mpro Inhibitors

Lecture notes in computer science, Год журнала: 2025, Номер unknown, С. 47 - 58

Опубликована: Янв. 1, 2025

Язык: 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, Год журнала: 2025, Номер 17(4), С. 491 - 491

Опубликована: Март 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.

Язык: Английский

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Identification of promising SARS-CoV-2 main protease inhibitor through molecular docking, dynamics simulation, and ADMET analysis

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 22, 2025

Abstract The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a major challenge global health. Targeting the main protease of virus (Mpro), which is essential for viral replication and transcription, offers promising approach therapeutic intervention. In this study, advanced computational techniques such as molecular docking dynamics simulations were used screen series antiviral compounds their potential inhibitory effect on Mpro. A comprehensive analysis from ChemDiv PubChem databases was performed. physicochemical properties, pharmacokinetics, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiles evaluated determine drug similarity safety. Compound 4896 − 4038 proved be most candidate. It exhibited favorable balance between weight (491.06) lipophilicity (logP 3.957), high intestinal absorption (92.119%), broad tissue distribution (VDss 0.529), indicating good oral bioavailability potential. Molecular studies showed that has strong binding affinity active site Mpro forms key interactions, hydrogen bonds, carbon-hydrogen pi-sulfur, multiple van der Waals pi-pi stacked bonds. energy comparable reference X77, efficacy. over 300 ns confirmed stability Mpro/4896 complex protein-ligand. Free landscape mapping MM/PBSA calculations further substantiated complex. Importantly, comparatively safety profile. summary, compound shows significant potent inhibitor, combining activity with pharmacokinetic profiles. These results support development agent in fight against warrants experimental validation clinical investigation.

Язык: Английский

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Pyrrolizines: natural and synthetic derivatives with diverse biological activities

International Journal of Clinical Medical Research, Год журнала: 2024, Номер 2(5), С. 171 - 184

Опубликована: Сен. 17, 2024

The pyrrolizine nucleus is a bicyclic ring system that consists of pyrrole fused to another pyrrolidin ring. It constitutes the basic skeleton in many natural and synthetic compounds with diverse biological activities such as anti-inflammatory, nootropic, antiemetic, antibacterial, antiviral, anticonvulsant, antiarrhythmic, anticancer activities. At least two these derivatives, ketorolac mitomycin C, have been approved for treatment inflammation cancer, respectively. Licofelone, dual inhibitor COX 5-LOX, was also evaluated clinical trials osteoarthritis. On other hand, large number pyrrolizine-based derivatives displayed activity against different types cancer cells. In this review, were classified based on their chemical structure into substituted, fused, spiro-pyrrolizine. mechanisms action included alkylation DNA, inhibition COX, or alteration permeability cytoplasmic membrane addition, pyrrolizines found act by inhibiting DNA replication, rRNA, Rac1 kinase, thioredoxin reductase, oncogenic kinases. last section review focuses reported X-ray crystal structures proteins. binding modes interactions licofelone illustrated review. To sum up, we anticipate data compiled will be useful researchers design potent

Язык: Английский

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The Application of Computer-Aided Drug Design Technology in Drug Development

Опубликована: Авг. 13, 2024

Язык: Английский

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