Biflavonoid as potential 3-chymotrypsin-like protease (3CLpro) inhibitor of SARS-Coronavirus

Hartini, Yustina Sri; Saputra, Bakti; Wahono, Bryan; Auw, Zerlinda; Indayani, Friska; Adelya, Lintang; Namba, Gabriel; Hariono, Maywan

doi:10.1016/j.rechem.2020.100087

Cited by 17 publications

(11 citation statements)

References 157 publications

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“…Amentoflavone is biflavonid, found to inhibit SARS-CoV-2 3CLpro with IC 50 143 µM [43] . Compounds bearing more carbonyl groups seem promising to be the protease inhibitor as it is designed to favour a higher nucleophilic attack by serine and cysteine proteases [55] , [56] . The complex of baicalein with SARS-CoV-2 3CLpro (PDB ID 6M2N) is one of the proofs that flavonoid is such an important feature for 3CLpro pharmacophore.…”

Section: Discussionmentioning

confidence: 99%

Potential SARS-CoV-2 3CLpro inhibitors from chromene, flavonoid and hydroxamic acid compound based on FRET assay, docking and pharmacophore studies

Hariono

Hariyono

Dwiastuti

et al. 2021

Results in Chemistry

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This present study reports some natural products and one hydroxamic acid synthetic compound which were previously reported as matrix metalloproteinase-9 (MMP-9) inhibitors to be evaluated for their inhibition toward severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro). This enzyme is one of the proteins responsible for this coronaviral replication. Two herbal methanolic extracts i.e., Averrhoa carambola leaves and Ageratum conyzoides aerial part demonstrate >50% inhibition at 1000 µg/mL. Interestingly, apigenin, one of flavonoids, demonstrates 92% inhibition at 250 µg/mL (925 µM) as well as hydroxamic acid compound, N -isobutyl- N -(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH), which shows 69% inhibition at 100 µM. The in vitro results are supported by the docking studies revealing that the binding mode of both compounds is mainly by interacting with GLU166 residue in the hydrophobic pocket of the 3CLpro. Pharmacophore mapping further supported the results by confirming that the in vitro activities of both compounds are due to their pharmacophore features employing hydrogen bond acceptor (HBA), hydrogen bond donor (HBD) and hydrophobic. Gas Chromatography-Mass Spectrometry (GC–MS) analysis reported chromene compounds in Ageratum conyzoides aerial part methanolic extract are potential to be this enzyme inhibitor candidate. These all results reflect their potencies to be SARS-CoV-2 inhibitors through 3CLpro inhibition mechanism.

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Section: Discussionmentioning

confidence: 99%

Potential SARS-CoV-2 3CLpro inhibitors from chromene, flavonoid and hydroxamic acid compound based on FRET assay, docking and pharmacophore studies

Hariono

Hariyono

Dwiastuti

et al. 2021

Results in Chemistry

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“…Re-docking analysis of this co-crystallized nonpeptidomimetic inhibitor on the binding site of the viral protease (PDB 6m2n) represents the similar pose with the reported X-ray crystallography, in which hydrogen bonding (H-bond) interaction was found between the carbonyl group of baicalein and Glu166, as well as the multiple H-bond between the two phenolic hydroxyl groups and Gly143. Hydrophobic interactions were found between the free phenyl ring of baicalein with Met49, Cys44, Pro52, and Tyr54 (Figure 2D) [22,23]. The steroid compounds showed binding modes mimicking the baicalein by polarly interacting with Glu166 and Gly143.…”

Section: Molecular Dockingmentioning

confidence: 98%

“…of baicalein and Glu166, as well as the multiple H-bond between the two phenolic hydroxyl groups and Gly143. Hydrophobic interactions were found between the free phenyl ring of baicalein with Met49, Cys44, Pro52, and Tyr54 (Figure 2D) [22,23]. The steroid compounds showed binding modes mimicking the baicalein by polarly interacting with Glu166 and Gly143.…”

Section: Molecular Dockingmentioning

confidence: 98%

GC-MS, LC-MS/MS, Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

et al. 2021

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This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.

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“…The world was shocked by the outbreak of SARS-Coronavirus-2 (SARS-CoV-2), which, so far, has lasted for almost two years. Although vaccines have been continually developed and distributed in order to urgently bring the pandemic to an end, there is no specific drug to combat the virus [134,135], as was the during outbreaks of dengue as well as chikungunya. In severe SARS-CoV-2 infections, large amounts of inflammation mediators such as tumour necrosis factor-α (TNF-α), macrophages, interleukins (ILs), interferons, and other factors, are present in the lungs, which is widely known as a cytokine storm.…”

Section: Perspectivementioning

confidence: 99%

The Future of Carica papaya Leaf Extract as an Herbal Medicine Product

et al. 2021

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Carica papaya (papaya) leaf extract has been used for a long time in a traditional medicine to treat fever in some infectious diseases such as dengue, malaria, and chikungunya. The development of science and technology has subsequently made it possible to provide evidence that this plant is not only beneficial as an informal medication, but also that it has scientifically proven pharmacological and toxicological activities, which have led to its formal usage in professional health care systems. The development of formulations for use in nutraceuticals and cosmeceuticals has caused this product to be more valuable nowadays. The use of good manufacturing practice (GMP) standards, along with the ease of registering this product facilitated by policies of the national government, will absolutely increase the value of papaya leaf extract as a vital nutraceutical and cosmeceutical products in the near future. In this article, we review the potential of papaya leaf extract to be a high-value commodity in terms of its health effects as well as its industrial benefits.

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Biflavonoid as potential 3-chymotrypsin-like protease (3CLpro) inhibitor of SARS-Coronavirus

Cited by 17 publications

References 157 publications

Potential SARS-CoV-2 3CLpro inhibitors from chromene, flavonoid and hydroxamic acid compound based on FRET assay, docking and pharmacophore studies

Potential SARS-CoV-2 3CLpro inhibitors from chromene, flavonoid and hydroxamic acid compound based on FRET assay, docking and pharmacophore studies

GC-MS, LC-MS/MS, Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

The Future of Carica papaya Leaf Extract as an Herbal Medicine Product

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