Reconstruction of the unbinding pathways of noncovalent SARS-CoV and SARS-CoV-2 3CLpro inhibitors using unbiased molecular dynamics simulations

Tiyoula, Fereshteh Noroozi; Aryapour, Hassan

doi:10.1371/journal.pone.0263251

Cited by 2 publications

(2 citation statements)

References 37 publications

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“…This protease is of interest among scientists in the development of antiviral drugs because it differs from the human proteases, which produce low side effects for patients. , The cleavage of polyprotein plays a crucial role in assembling of the viral replication transcription complex (RTC) for the initiation step of viral replication. The structure of SARS-CoV-2 3CL Pro is a dimer protein characterized by three subdomains of 306 amino acid residues . The active site is located in a cleft between domain I (residues 8–99) and domain II (residues 100–183) and possesses a catalytic dyad at His41 and Cys145 .…”

Section: Introductionmentioning

confidence: 99%

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

Khamto

Utama

Tateing

et al. 2023

J. Chem. Inf. Model.

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

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Section: Introductionmentioning

confidence: 99%

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

Khamto

Utama

Tateing

et al. 2023

J. Chem. Inf. Model.

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“… 24–27 Although many covalent and noncovalent inhibitors have been designed to inhibit this enzyme, none have been FDA approved. 28 …”

Section: Introductionmentioning

confidence: 99%

Identification of Drug Combination Therapies for SARS-CoV-2: A Molecular Dynamics Simulations Approach

Abdel-Halim¹,

Hajar²,

Hasouneh³

et al. 2022

DDDT

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Purpose The development of effective treatments for coronavirus infectious disease 19 (COVID-19) caused by SARS-Coronavirus-2 was hindered by the little data available about this virus at the start of the pandemic. Drug repurposing provides a good strategy to explore approved drugs’ possible SARS-CoV-2 antiviral activity. Moreover, drug synergism is essential in antiviral treatment due to improved efficacy and reduced toxicity. In this work, we studied the effect of approved and investigational drugs on one of SARS-CoV-2 essential proteins, the main protease (M pro ), in search of antiviral treatments and/or drug combinations. Methods Different possible druggable sites of M pro were identified and screened against an in-house library of more than 4000 chemical compounds. Molecular dynamics simulations were carried out to explore conformational changes induced by different ligands’ binding. Subsequently, the inhibitory effect of the identified compounds and the suggested drug combinations on the M pro were established using a 3CL protease (SARS-CoV-2) assay kit. Results Three potential inhibitors in three different binding sites were identified; favipiravir, cefixime, and carvedilol. Molecular dynamics simulations predicted the synergistic effect of two drug combinations: favipiravir/cefixime, and favipiravir/carvedilol. The in vitro inhibitory effect of the predicted drug combinations was established on this enzyme. Conclusion In this work, we could study one of the promising SARS-CoV-2 viral protein targets in searching for treatments for COVID-19. The inhibitory effect of several drugs on M pro was established in silico and in vitro assays. Molecular dynamics simulations showed promising results in predicting the synergistic effect of drug combinations.

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Reconstruction of the unbinding pathways of noncovalent SARS-CoV and SARS-CoV-2 3CLpro inhibitors using unbiased molecular dynamics simulations

Cited by 2 publications

References 37 publications

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

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

Identification of Drug Combination Therapies for SARS-CoV-2: A Molecular Dynamics Simulations Approach

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Reconstruction of the unbinding pathways of noncovalent SARS-CoV and SARS-CoV-2 3CLpro inhibitors using unbiased molecular dynamics simulations

Cited by 2 publications

References 37 publications

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

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

Identification of Drug Combination Therapies for SARS-CoV-2: A Molecular Dynamics Simulations Approach

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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

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