Dataset Information

Structural insights into inhibition of PRRSV Nsp4 revealed by structure-based virtual screening, molecular dynamics, and MM-PBSA studies.

ABSTRACT:

Background

Porcine reproductive and respiratory syndrome respiratory sickness in weaned and growing pigs, as well as sow reproductive failure, and its infection is regarded as one of the most serious swine illnesses worldwide. Given the current lack of an effective treatment, in this study, we identified natural compounds capable of inhibiting non-structural protein 4 (Nsp4) of the virus, which is involved in their replication and pathogenesis.

Results

We screened natural compounds (n = 97,999) obtained from the ZINC database against Nsp4 and selected the top 10 compounds for analysing protein-ligand interactions and physicochemical properties. The five compounds demonstrating strong binding affinity were then subjected to molecular dynamics simulations (100 ns) and binding free energy calculations. Based on analysis, we identified four possible lead compounds that represent potentially effective drug-like inhibitors.

Conclusions

These methods identified that these natural compounds are capable of inhibiting Nsp4 and possibly effective as antiviral therapeutics against PRRSV.

SUBMITTER: Pathak RK

PROVIDER: S-EPMC8864930 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Structural insights into inhibition of PRRSV Nsp4 revealed by structure-based virtual screening, molecular dynamics, and MM-PBSA studies.

Pathak Rajesh Kumar RK Seo Young-Jun YJ Kim Jun-Mo JM

Journal of biological engineering 20220222 1

<h4>Background</h4>Porcine reproductive and respiratory syndrome respiratory sickness in weaned and growing pigs, as well as sow reproductive failure, and its infection is regarded as one of the most serious swine illnesses worldwide. Given the current lack of an effective treatment, in this study, we identified natural compounds capable of inhibiting non-structural protein 4 (Nsp4) of the virus, which is involved in their replication and pathogenesis.<h4>Results</h4>We screened natural compound ...[more]

PMID: 35193698

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Project description:All the plants and their secondary metabolites used in the present study were obtained from Ayurveda, with historical roots in the Indian subcontinent. The selected secondary metabolites have been experimentally validated and reported as potent antiviral agents against genetically-close human viruses. The plants have also been used as a folk medicine to treat cold, cough, asthma, bronchitis, and severe acute respiratory syndrome in India and across the globe since time immemorial. The present study aimed to assess the repurposing possibility of potent antiviral compounds with SARS-CoV-2 target proteins and also with host-specific receptor and activator protease that facilitates the viral entry into the host body. Molecular docking (MDc) was performed to study molecular affinities of antiviral compounds with aforesaid target proteins. The top-scoring conformations identified through docking analysis were further validated by 100 ns molecular dynamic (MD) simulation run. The stability of the conformation was studied in detail by investigating the binding free energy using MM-PBSA method. Finally, the binding affinities of all the compounds were also compared with a reference ligand, remdesivir, against the target protein RdRp. Additionally, pharmacophore features, 3D structure alignment of potent compounds and Bayesian machine learning model were also used to support the MDc and MD simulation. Overall, the study emphasized that curcumin possesses a strong binding ability with host-specific receptors, furin and ACE2. In contrast, gingerol has shown strong interactions with spike protein, and RdRp and quercetin with main protease (Mpro) of SARS-CoV-2. In fact, all these target proteins play an essential role in mediating viral replication, and therefore, compounds targeting aforesaid target proteins are expected to block the viral replication and transcription. Overall, gingerol, curcumin and quercetin own multitarget binding ability that can be used alone or in combination to enhance therapeutic efficacy against COVID-19. The obtained results encourage further in vitro and in vivo investigations and also support the traditional use of antiviral plants preventively.

Dataset Information

Structural insights into inhibition of PRRSV Nsp4 revealed by structure-based virtual screening, molecular dynamics, and MM-PBSA studies.

Background

Results

Conclusions

Publications

Structural insights into inhibition of PRRSV Nsp4 revealed by structure-based virtual screening, molecular dynamics, and MM-PBSA studies.

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