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Natural Products as Potential Lead Compounds for Drug Discovery Against SARS-CoV-2.

ABSTRACT: For the past 2 years, the coronavirus responsible for the COVID-19 infection has become a world pandemic, ruining the lives and economies of several nations in the world. This has scaled up research on the virus and the resulting infection with the goal of developing new vaccines and therapies. Natural products are known to be a rich source of lead compounds for drug discovery, including against infectious diseases caused by microbes (viruses, bacteria and fungi). In this review article, we conducted a literature survey aimed at identifying natural products with inhibitory concentrations against the coronaviruses or their target proteins, which lie below 10 µM. This led to the identification of 42 compounds belonging to the alkaloid, flavonoid, terpenoid, phenolic, xanthone and saponin classes. The cut off concentration of 10 µM was to limit the study to the most potent chemical entities, which could be developed into therapies against the viral infection to make a contribution towards limiting the spread of the disease.

SUBMITTER: Ebob OT

PROVIDER: S-EPMC8435765 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Natural Products as Potential Lead Compounds for Drug Discovery Against SARS-CoV-2.

Ebob Oyere Tanyi OT Babiaka Smith B SB Ntie-Kang Fidele F

Natural products and bioprospecting 20210913 6

For the past 2 years, the coronavirus responsible for the COVID-19 infection has become a world pandemic, ruining the lives and economies of several nations in the world. This has scaled up research on the virus and the resulting infection with the goal of developing new vaccines and therapies. Natural products are known to be a rich source of lead compounds for drug discovery, including against infectious diseases caused by microbes (viruses, bacteria and fungi). In this review article, we cond ...[more]

PMID: 34515981

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Project description:The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 μM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 μM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.

Project description:SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, -8.7 kcal/mol), PLpro (binding energy, -7.9 kcal/mol), and Nucleocapsid (binding energy, -7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, -24.42 kcal/mol and MMPBSA, -10.80 kcal/mol), PLpro (MMGBSA, -48.69 kcal/mol and MMPBSA, -38.17 kcal/mol) and Nucleocapsid (MMGBSA, -30.05 kcal/mol and MMPBSA, -25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, -22.44 kcal/mol), PLpro (mean, -25.46 kcal/mol), and Nucleocapsid (mean, -23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

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Natural Products as Potential Lead Compounds for Drug Discovery Against SARS-CoV-2.

Publications

Natural Products as Potential Lead Compounds for Drug Discovery Against SARS-CoV-2.

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