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. 2022 Sep 27;27(19):6374. doi: 10.3390/molecules27196374

Table 1.

Recent in silico studies of flavonoids against COVID-19.

Methods No. of Compounds Tested Structure
(PDB ID)		 Description Binding Affinity for Molecules (Kcal/mol) Results References
SWISS DOCK 35 6LU7

  • Anti-viral drugs and 35 compounds were screened against chymotyripsin-like protease (3CLpro).

  • UCSF chimera was used to visualize the interaction (hydrophobic bonds and H-bonds) between ligands and the amino acid of the targeted protein.

  • ProTox was used to evaluate toxicity.

  • Cordifolin: −8.77

  • Anisofolin A: −8.72

  • Apigenin-7-glycoside: −8.36

  • Luteolin: −8.35

  • Laballenic acid: −8.13

  • Quercetin: −8.04

  • Luteolin-4-glucoside: −7.87

  • Apigenin-7-glycoside, luteolin, quercetin, and luteolin-4-glucoside showed least binding energy, meaning higher binding affinity with amino acids of protease.

 [118]
Auto Dock Vina 19 6LU7 (main protease (Mpro))
 
6VXX (spike glycoprotein)

  • Molecular docking approach was used to study inhibition of two COVID-19 proteins, i.e., main protease (Mpro) and spike glycoprotein by bioactive compounds.

  • Lipinski’s rule of five was used to determine the efficacy of compounds as potential drugs.

  • Nelfinavir, chloroquine, and hydroxyl chloroquine sulfate drugs were used as positive controls.

  • Hesperidin: −10.4 (spike glycoprotein), −8.3 (main protease)

  • Nabiximols: −10.2 (spike glycoprotein), −8.0 (main protease)

  • Pectolinarin: −9.8 (spike glycoprotein), −8.2 (main protease)

  • Epigallocatechin gallate: −9.8 (spike glycoprotein), −7.8 (main protease)

  • Rhoifolin: −9.5 (spike glycoprotein), 8.2 (main protease)

  • Hesperidine, cannabinoids, pectolinarin, epigallocatechin gallate. and rhoifolin showed better inhibitory activity for spike glycoprotein than control drugs.

  • Hesperidine, cannabinoids, pectolinarin, and rhoifolin showed better inhibitory activity for main protease (Mpro) than chloroquine and hydroxychloroquine sulfate drugs and almost similar to nelfinavir.

  • However, hesperidine, pectolinarin, and rhoifolindonot follow Lipinski’s rule.

  • Low bioavailability of some compounds, i.e., hesperidine, cannabinoids, and rhoifolin, may pose a problem during drug design.

 [119]
MOE2010 -- 6LU7 (main protease (Mpro))
6VW1 (PD-ACE2)
6LXT (RBD-S)

  • Compounds evaluated:

  • (1)

    Curcuminoids from Curcuma sp.

  • (2)

    Methoxy flavonoids from Citrus sp.

  • (3)

    Phenolic compounds from Caesalpinia sappan.

  • (4)

    Phenylpropanoid compounds from Alpinia galanga.

  • Three protein targets were selected:

  • (1)

    Receptor binding domain of spike protein (RBD-S).

  • (2)

    Angiotension converting enzyme-2 receptor at protease domain (PD-ACE2).

  • (3)

    Main protease (Mpro).

  • Docking score was used to evaluate binding affinity.

  • Curcumin: −11.82 (main protease), −8.39 (spike glycoprotein), −9.04 (RBD-ACE2)

  • Hesperitin: −12.36 (main protease), −9.08 (spike glycoprotein), −6.72 (RBD-ACE2)

  • Hesperidin: −13.51 (main protease), −9.61 (spike glycoprotein), −9.50 (RBD-ACE2)

  • Naringenin: −12.44 (main protease), −7.40 (spike glycoprotein), −7.69 (RBD-ACE2)

  • Brazilin: −12.36 (main protease), −7.50 (spike glycoprotein), −7.49 (RBD-ACE2)

  • Galangin: −12.96 (main protease), −7.89 (spike glycoprotein), −7.60 (RBD-ACE2)

  • Hesperidin showed lowest binding energy for all three protein targets, i.e., −13.51 (main protease), −9.61 (RBD-S) and −9.50 (PD-ACE2).

  • Docking score of hesperidin is less than lopinavir, meaning better interaction with protein targets.

  • Other compounds also showed good affinity compared to reference compounds, but less than hesperidin.

  • Citrus compounds showed better potential in inhibiting the development of COVID-19 followed by Alpinia galangal, Caesalpinia sappan, and Curcuma.

 [120]
ClusPro (docking between spike protein fragment and human ACE2 receptor)
SWISS DOCK (between compounds and the bound structure of the spike protein fragment and human ACE2 receptor)		 5

  • Herperidin, emodin, anthroquinone, rhein, and chrysin phytochemicals were used in this study.

  • Hesperidin: −8.99

  • Emodin: −6.19

  • Anthroquinone: −6.15

  • Rhein: −8.73

  • Chrysin: −6.87

  • Hesperidin, emodin, and chrysin are considered as potential candidates to treat COVID-19.

  • Hesperidin binds with the amino acids of the H1 and H2 helix of the ACE2 receptor protein.

  • Emodin binds with the amino acids of the H2 helix of the ACE2 receptor protein.

  • Anthroquinone and rhein are not considered as therapeutic agents against COVID-19 because of no interactions.

  • Chrysin interacts with the amino acids of the H5 helix of the ACE2 receptor protein.

 [121]
Autodock 4.2 13 6LU7

  • Docking score and binding energy were used to evaluate binding affinity.

  • Lipinski’s rule of five was used to determine the efficacy of compounds as potential drugs.

  • Kaempferol: −8.58

  • Quercitin: −8.47

  • Luteolin-7-glucoside: −8.17

  • Demethoxycurcumin: −7.99

  • Naringenin: −7.89

  • Apigenin-7-glucoside: −7.83

  • Oleuropein: −7.31

  • Curcumin: −7.05

  • Catechin: −7.24

  • Epicatechin-gallate: −6.67

  • Mpro of COVID-19 shares 96% similarity with Mpro of SARS-CoV.

  • Order of inhibition potential of selected compounds:

nelfinavir > lopanavir > kaemferol > quercetin > luteolin-7-glucoside > demethoxycurcumin > naringenin > apigenin-7-glucoside > oleuropein > curcumin > catechin > epigallocatechin > zinger > allicin.

  • All the compounds follow Lipinski’s rule of five.

 [22]
Auto Dock Vina 72 6LU7

  • 3CL pro was used as the active site for docking.

  • Binding energy was calculated for checking binding affinity.

  • ADME and toxicology of flavonoids were also performed.

  • Amentoflavone: −9.0

  • Gallocatechingallate: −8.3

  • Diosmin: −9

  • Epigallocatechin gallate: −8.3

  • Hidrosmin: −8.9

  • Catechingallate: −8.4

  • Elsamitrucin: −8.3

  • Pectolinaren: −8.3

  • Silibinin: −8.1

  • Oriemtim: −8.0

  • Isoquercetin= −8.0

  • All the flavonoids except auraptene have binding energy <−6 kcal/mol.

  • Top ten flavonoids with lowest binding energy.

  • The majority of flavonoids also had high predicted probabilities of being toxic to fathead minnows (FHM), honey bees (HBT), and Tetrahymena pyriformis (TPT), which should not be a concern for humans as they are all commonly consumed flavonoids.

 [23]
Auto Dock Vina 14 6LU7

  • Mpro was used as the active site for docking.

  • Polar H-bond was added to Mpro before docking followed by the addition of Kollman charges.

  • Pymol 4.3.0, Ligplot+, and protein–ligand interaction profiler was used to analyze docking results.

  • Hesperidin

  • Rutin

  • Diosmin

  • Apiin

  • Diacetylcurcumin

  • Procyanidin b2 and mangiferin showed highest binding affinity with Mpro with binding energy of −9.4 Kcal/mol and −8.5 Kcal/mol, respectively.

  • Azithromycin, an antibiotic, showed lowest binding energy, i.e., −13.4 kcal/mol.

  • Both flavonoids form multiple H-bonds with the main chain of the residue in the substrate binding pocket, which inhibits the binding site of the inhibitor.

  • Both flavonoids have binding affinity greater than hydroxyquinone, flavipiravir, and ramdesivir.

 [122]
Swiss Dock 18 6LU7

  • 18 compounds were extracted from 11 different species.

  • Main focus was given to compounds that possess anti-malarial or anti-viral activity.

  • Lipophilicity (log P) and aqueous solubility (log S) were calculated using ALOGPS 2.1 program.

  • Nictoflorin: −9.18

  • Astragalin: −8.68

  • Lupeol: −8.28

  • Aloenin: −9.13

  • Aloesin: −8.79

  • Berberine: −8.67

  • Sitosterol: −8.42

  • Curcumin: −8.44

  • Harsingar, Aloe vera, and giloy herbal plant compounds showed maximum affinity to Mpro of COVID-19.

  • Nictofloein (−9.18 kcal/mol), astragalin (−8.68 kcal/mol), and lupeol (−8.28 kcal/mol) were extracted from harsingar; aloenin (−9.13 kcal/mol) and aloesin (−8.79 kcal/mol) were extracted from Aloe Vera; berbirine (−8.67 kcal/mol) and sitosterol (−8.42 kcal/mol) were extracted from giloy.

  • Most compounds have log-P values in the range of 2.64–4.95.

  • Lupeol, sitosterol, ursolic acid, and cannabidiol have log-P in the range of 5.12–7.27, which means they possess high hydrophobicity and poor absorption, whereas nictoflowin, astragalin, aloenin, aloesin, and quercetin have log-P (0.05–1.81), which means high absorption.

  • Most compounds’ log-S value was in the range of −1 to −5, which implies less bioavailability.

  • Nictoflowin, astragalin, aloenin, aloesin, and quercetin were considered as more biologically potent compounds asprotease inhibitors, as well as having good bioavailability.

 [123]
Auto Dock Vina 7173 purchasable drugs and 4574 unique compounds and their stereoisomers 2DUC

  • High-resolution apoenzyme stricture of SARS-CoV-2 Mpro was used as the template.

  • MTiopen screen web service was used for screening compounds.

  • Diosmin: −10.1

  • Hesperidin: −10.1

  • MK-3207: −10.1

  • Venetoclax: −10.0

  • Dihydroergocristine: −9.8

  • Bolazine: −9.8

  • R428: −9.8

  • Ditercalinium: −9.8

  • Etoposide-phosphate: −9.8

  • Hesperidin and diosmin fit well in the docking site and block the active site of the virus.

  • Hesperidin and its 38 different stereoisomeric forms all were among the top scores.

  • Good inhibitor of SARS-CoV 3CLpro with an IC50 value of 8.3 µM, whereas some of the mild adverse reactions of these flavonoids were also reported, such as stomach pain and nausea,

 [21]