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Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database.

ABSTRACT: Background: The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. Methodology: A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Conclusion: Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.

SUBMITTER: Novak J

PROVIDER: S-EPMC7798421 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database.

Novak Jurica J Rimac Hrvoje H Kandagalla Shivananda S Grishina Maria A MA Potemkin Vladimir A VA

Future medicinal chemistry 20210108 4

Background: The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. Methodology: A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Conclusion: Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this stu ...[more]

PMID: 33415989

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Project description:BackgroundA global pandemic owing to COVID-19 infection has created havoc in the entire world. The etiological agent responsible for this viral outbreak is classified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Still, there's no specific drug or preventive medication to treat SARS-CoV-2. This study was designed to demonstrate the efficacy of some anti-viral peptides obtained from a plant database i.e., PlantPepDB as potential ACE-2-Spike (S) protein complex neutralizers using a structure-based drug designing approach.MethodA total of 83 anti-viral plant peptides were screened from a peptide database i.e. PlantPepDB based on their reported anti-viral activities against various viral strains. In order to screen peptides that may potentially interfere with ACE-2 and S complex formation, molecular docking studies were conducted using the flare module of Cresset software and subsequently, analysed the crucial interactions between the peptides and S complexes and ACE-2/S complex. Herein, the interactions and docking scores obtained for ACE-2/S complex were considered as references. The S-peptides complexes which displayed superior interactions and docking scores than reference complex i.e., ACE2-S were considered as final hits. The Molecular dynamics studies were conducted for a period of 30 ns for each of the final hit/S complex to understand the interaction stability and binding mechanism of designed peptides.ResultsThe molecular docking results revealed that five peptides including Cycloviolacin Y3, Cycloviolacin Y1, White cloud bean defensin, Putative defensin 3.1, and Defensin D1 showed superior docking scores (i.e. -1372.5 kJ/mol to -1232.6 kJ/mol) when docked at the ACE2 binding site of S-protein than score obtained for the complex of ACE-2 and S protein i.e. -1183.4 kJ/mol. Moreover, these top five peptides manifested key interactions required to prevent the binding of S protein with ACE2. The molecular dynamics simulation study revealed that two of these five peptides i.e. Cycloviolacin Y3 and Cycloviolacin Y1 displayed minimal RMSD fluctuations.ConclusionsThe current structure-based drug-designing approach shows the possible role of anti-viral plant peptides as potential molecules to be explored at the initial stage of viral pathogenesis.

Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), known to cause the disease COVID-19, was declared a pandemic in early 2020. The objective of this review was to collate information regarding the potential of plants and natural products to inhibit coronavirus and targets associated with infection in humans and to highlight known drugs, which may have potential activity against SARS-CoV-2. Due to the similarity in the RNA genome, main proteases, and primary host receptor between SARS-CoV and SARS-CoV-2, a review was conducted on plants and secondary metabolites, which have shown activity against SARS-CoV. Numerous scientific reports on the potential of plants and secondary metabolites against SARS-CoV infection were found, providing important information on their possible activity against SARS-CoV-2. Based on current literature, 83 compounds have been identified with the potential to inhibit COVID-19. The most prominent selectivity was found for the alkaloid, lycorine, the lignan, savinin, and the abietane terpenoid, 8-beta-hydroxyabieta-9(11),13-dien-12-one with selectivity index values greater than 945, 667, and 510, respectively. Plants and their secondary metabolites, with activity against targets associated with the SARS-CoV infection, could provide valuable leads for the development into drugs for the novel SARS-CoV-2. The prospects of using computational methods to screen secondary metabolites against SARS-CoV targets are briefly discussed, and the drawbacks have been highlighted. Finally, we discuss plants traditionally used in Southern Africa for symptoms associated with respiratory viral infections and influenza, such as coughs, fever, and colds. However, only a few of these plants have been screened against SARS-CoV. Natural products hold a prominent role in discovering novel therapeutics to mitigate the current COVID-19 pandemic; however, further investigations regarding in vitro, in vivo, pre-clinical, and clinical phases are still required.

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Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database.

Publications

Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database.

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