Discovery of Natural Bisbenzylisoquinoline Analogs from the Library of Thai Traditional Plants as SARS-CoV-2 3CL^Pro Inhibitors: In Silico Molecular Docking, Molecular Dynamics, and In Vitro Enzymatic Activity

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(7), P. 2104 - 2121

Published: Jan. 17, 2023

The emergence of SARS-CoV-2 in December 2019 has become a global issue due to the continuous upsurge patients and lack drug efficacy for treatment. 3CLPro is one most intriguing biomolecular targets among scientists worldwide developing antiviral drugs its relevance viral replication transcription. Herein, we utilized computer-assisted screening investigate 326 natural products from Thai traditional plants using structure-based virtual against 3CLPro. Following screening, top 15 compounds based on binding energy their interactions with key amino acid Cys145 were obtained. Subsequently, they further evaluated protein–ligand complex stability via molecular dynamics simulation free calculation mechanics Poisson–Boltzmann surface area (MM-PBSA) approaches. drug-likeness ADME/Tox assessments, seven bisbenzylisoquinolines obtained, including neferine (3), liensinine (4), isoliensinine (5), dinklacorine (8), tiliacorinine (13), 2′-nortiliacorinine (14), yanangcorinine (15). These computationally showed higher affinity than native N3 GC-373 inhibitors attained stable active site 3CLpro during 100 ns (MD) simulation. Moreover, vitro enzymatic assay that could experimentally inhibit To our delight, (5) isolated Nelumbo nucifera demonstrated highest inhibition protease activity IC50 value 29.93 μM low toxicity Vero cells. Our findings suggested bisbenzylisoquinoline scaffolds be potentially used as an vivo model development effective anti-SARS-CoV-2 drugs.

Language: Английский

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Nirmatrelvir treatment of SARS‐CoV‐2‐infected mice blunts antiviral adaptive immune responses

EMBO Molecular Medicine, Journal Year: 2023, Volume and Issue: 15(5)

Published: March 22, 2023

Abstract Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS‐CoV‐2 pandemic. Nirmatrelvir—an orally available inhibitor 3‐chymotrypsin‐like cysteine protease—has been shown reduce risk progression severe COVID‐19. However, impact nirmatrelvir treatment on development SARS‐CoV‐2‐specific adaptive immune responses is unknown. Here, by using mouse models infection, we show that administration blunts antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir‐treated mice recruited significantly fewer memory B cells infected lungs mediastinal lymph nodes, respectively. Together, data highlight a potential negative with important implications for clinical management might help explain virological and/or symptomatic relapse after completion reported in some individuals.

Language: Английский

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Cys44 of SARS-CoV-2 3CLpro affects its catalytic activity

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 139590 - 139590

Published: Jan. 1, 2025

Language: Английский

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Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction

Virology, Journal Year: 2025, Volume and Issue: 604, P. 110394 - 110394

Published: Jan. 11, 2025

Language: Английский

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The Chiral 5,6-Cyclohexane-fused Uracil Ring-System: a Molecular Platform with Promising Activity against SARS-CoV-2

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 286, P. 117302 - 117302

Published: Jan. 21, 2025

Language: Английский

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