Table 5 Potential polyphenolic compounds as antiviral agents against SARS-CoV-2

Phillyrin (KD-1)

Forsythia suspensa

SARS-CoV-2 and HCoV-229E

In vitro using cytopathic effect and plaque reduction assay in Vero E6 cells

IC₅₀ against SARS-CoV-2 and HCoV-229E is 63.90 and 64.53 mg/mL

[256]

Phillyrin (KD-1)

Forsythia suspensa

SARS-CoV-2 and HCoV-229E

In vitro based on pro-inflammatory cytokine expression levels in Huh-7 cells by RT-PCR assay

Phillyrin reduced the production of proinflammatory cytokines at mRNA levels and reduced the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα

[256]

Cannabidiol and Δ⁹-tetrahydrocannabinol

Cannabis sativa L. (Chongsam, leaves)

SARS-CoV-2 (βCoV/KOR/ KCDC03/2020)

In vitro using screening assay in Vero cells

IC₅₀ of 7.91 mM and 10.25 mM

[257]

Pelargonidin

SARS-CoV-2 Spike protein

In vitro using Spike/ACE2 Inhibitor Screening Assay Kit and using plaque assay in Vero E6 cells

At 50 mM reduces Spike binding to ACE2 by about 40%. Plaque assay reduces virus entry by about 70% at 100 mM

[258]

Juglanin

3a-protein channel of SARS-CoV

In vitro using Voltage-clamp experiments on SARS-3a protein

IC₅₀ of 2.3 mM

[259]

Emodin

Genus Rheum and Polygonum

SNE (spike and envelope gene)-3a protein of SARS-CoV

In vitro using Voltage-clamp experiments on SARS-3a protein

IC₅₀ of 20 mM

[249]

Emodin

SARS-CoV spike protein

In vitro using luciferase assay

IC₅₀ of 200 mM

[250]

ThE (composed of green tea catechin and epigallocatechin gallate EGCG; total catechins were 85–95% and total EGCG was 65–70%, caffeine < 0.5%)

Product from Mitsui Norin Co. Ltd

SARS-CoV-2

In vivo using clinical trials. Ten patients were treated for 15 days sessions of inhalation plus three capsules per day (total catechin, 840 mg; total EGCG, 595 mg)

Seven of ten patients switched to a negative SARS-CoV-2 nasopharyngeal swab test in a range of 6–13 days

[260]

Curcumin

Hesperidin

Quercetin

hydroxychloroquine

From chemical manufacturers

SARS-CoV-2 from hCoV-19/Egypt/NRC-3/2020 SARS-CoV-2 virus (Accession

Number on GSAID: EPI_ISL_430820)

In vitro using plaque reduction assay in Vero E6 cells

IC₅₀ values: Curcumin 0.44 mM

Hesperidin 13.25 mM

Quercetin 18.2 mM

Hydroxychloroquine 1.72 mM

[194, 261]

Gallocatechin gallate (GCG)

Epigallocatechin gallate (EGCG)

Quercetin

From Sigma-Aldrich

Recombinant SARS 3CLpro transformed and expressed in Pichia pastoris GS115 based on GenBank accession no. AY274119

In vitro: proteolytic activity based on fluorescence resonance energy transfer (FRET) assay

In silico: using Autodock Tools software with a ligand number of 3CLpro is 2ZU5

IC₅₀ of:

GCG = 47 mM

EGCG = quercetin = 73 mM

The binding energy of:

GCG = − 14.1 kcal/mol, EGCG = − 11.7 kcal/mol, quercetin = − 10.2 kcal/mol

SAR: EGCG and CGC have a galloyl moiety at the 3-OH position to interact with the 3CLpro active site pocket

[248]

Myricetin

SARS-CoV-2 Mpro

In vitro using a proteolytic assay based on FRET

In silico: using AMBER18 with ligand number of 3CLpro is 6LZE

In vivo: pulmonary inflammation in bleomycin treated mice

IC₅₀ 3.684 ± 0.076 μM

The binding free energy is -32.98 kcal/mol

Myrcetin inhibits the infiltration of inflammatory cells and secretion of inflammatory factors in the lung

[262]

Ginkgolic acid (GA) and anacardic acid (AA)

SARS-CoV-2 PLpro, SARS-CoV-2 CLpro, isolated SARS2-CoV-2 USA-WA1/2020

In vitro using an enzymatic assay based on fluorometric peptide (FRET) assay. Antiviral determination using plaque reduction assay on Vero-E6 cells

In silico using Autodock Vina with ligand 6m2n and 6WX4

IC₅₀ against PLpro: GA = 16.30 ± 0.64 and AA = 17.08 ± 1.20 mM

IC₅₀ against 3CL pro: GA = 1.79 ± 0.58 and AA = 2.07 ± 0.35 mM

EC₅₀ against SARS-CoV-2: GA = 8.3 ± 0.03 mM and AA = 9.0 ± 2.5 mM

Inhibition at 7.5 mM: GA = 42% and AA = 13%

Binding affinity of GA to 3CLpro and PLpro is -5.3 and -4.9 kcal/mol

[263]

Curcumin, brazilin, and theaflavin-3,3’-digallate

SARS-CoV-2 RBD

In vitro using SARS-CoV-2 Surrogate Virus Neutralization Test Kit

% binding with RBD at 0.1 mg/mL = 100 ± 0.2; 100 ± 0.1; and 100 ± 0.1

[34]

Broussochalcone A (BcA); Papyriflavonol A (PA); 3’-(3-methylbut-2-enyl)-3’,4’,7-trihydroxy flavane (tHF); Broussoflavan A (BfA); Kazinol F (KF); Kazinol J (KJ)

Broussonetia papyrifera

SARS CoV-2 Mpro

In silico using AutoDock Vina on SARS-CoV-2 Mpro (6LU7)

Binding affinity (kcal/mol):

BcA =− 8.1

PA =− 7.9

tHF =− 8.2

BfA =− 7.8

KF =− 8.1

KJ =− 8.0

[264]

Kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, epicatechin-gallate

From chemical manufacturers

SARS-CoV-2 3CLpro/Mpro and SARS-CoV 3CLpro/Mpro

In silico using

Autodock 4.2 with Lamarckian Genetic Algorithm on Mpro (6LU7 and 2GTB)

These listed compounds were ranked by affinities (ΔG)

[265]

Curcumin

Hesperidin

Quercetin

hydroxychloroquine

From chemical manufacturers

SARS-CoV-2: S spike protein and main protease

In silico using MOE 2019.012 suite with S spike protein (6VW1) and Mpro (6LU7)

Binding score to S protein and Mpro:

Curcumin − 7.02 and − 7.28 kcal/mol

Hesperidin − 7.92 and − 8.37 kcal/mol

Quercetin − 6.48 and − 6.23 kcal/mol

Hydroxychloroquine -6.60 and  − 7.05 kcal/mol

[194]

Gallocatechin gallate (GCG)

Epicatechin gallate (ECG)

Epigallocatechin gallate (EGCG)

Catechin gallate (CG)

Epicatechin (EC)

Catechin

Gallocatechin (GC)

Epigallocatechin (EGC)

SARS-CoV-2 main protease

In silico using AutoDock Vina with Mpro (6LU7)

Three best binding energies:

GCG − 9.0 kcal/mol

ECG − 8.2 kcal/mol

EGCG − 7.6 kcal/mol

[266, 267]

Rutin

SARS-CoV-2 Mpro (6LU7 and 6YNQ)

In silico using Glide module

Docking score: above − 7.0; − 8.7; − 9.16 kcal/mol

[169]–[171]

Calceolarioside B

SARS-CoV-2 Mpro (6LU7), Nsp15 endoribonuclease (6VWW), coronavirus fusion protein (6LXT), SARS-CoV-2 spike ectodomain (6VYB)

In silico using Molegro Virtual Docker

MolDock score:

− 191.295

− 164.77

− 141.587

− 153.135

[268]

5-O-D-glucopyranosyl-4'-hydroxy-7-methoxy-4-phenylcoumarin

SARS-CoV-2 Nsp15 endoribonuclease (6WXC)

In silico using windows MOE

Binding energy of − 10.1 kcal/mol

[269]

Luteolin 7-O-β-glucopyranoside (cynaroside), acacetin 7-O-β-rutinoside (linarin) and isoacteoside (isoverbascoside)

Amphilophium paniculatum (L.) Kunth (leaves)

SARS-CoV-2 Mpro (7BUY)

In silico using Molecular Operating Environment (MOE) 2019.0102

Energy score of − 9.54, − 8.54, − 8.46 kcal/mol

[270]

Cannabidiol and Δ⁹-tetrahydrocannabinol

SARS-CoV-2 (6LU7)

In silico using Autodock and Vina

Binding energy in Autodock is − 10.53 and − 10.42 kcal/mol, while in Vina is − 6.43 and − 7.13 kcal/mol

[257]

Cyanidin, malvidin, pelargonidin, peonidin, petunidin

Pimpinella anisum L. (anise)

SARS-CoV-2 3CLpro (6LU7)

In silico using AutoDock Vina

Binding energy: − 8.1; − 8.0; − 8.0; − 7.7; − 7.5 kcal/mol

[271]

Procyanidin b2 and mangiferin

Chincona pubescenc. and from mango tree

SARS-CoV-2 3CLpro (6LU7)

In silico using AutoDock Vina

Binding affinity: -9.4 and -8.5 kcal/mol

[272]

Heptafuhalol A

SARS-CoV-2 Mpro (6LU7)

In silico using Vina and Autodock

Average ΔG = − 14.6 kcal/mol

[273]

Oolonghomobisflavan-A

SARS-CoV-2 Mpro (6Y2F)

In silico using GROMACS

Binding free energy on MM-PBSA calculation: -256.875 kj/mol

[274]

Epigallocatechin gallate

Green tea

SARS-CoV-2 Mpro (6LU7), NSP15 endoribonuclease (6VWW), free enzyme Mpro (6Y2E), and 2019-nCoV HR2 domain (6LVN), post fusion core of S2 subunit (6LXT), prefusion spike glycoprotein (6VSB), chimeric receptor-binding domain complexed with hACE2 (6VW1)

In silico using AutoDock

Binding energy (kcal/mol):

6LU7 = − 6.99; 6LVN = − 4.90; 6LXT = − 7.57; 6VSB = − 7.26;

6VWW = − 8.38; 6Y2E = − 9.30; 6VW1 = − 8.66

[275]

Theaflavin digallate

SARS-CoV-2 Mpro (6LU7)

In silico using GLIDE

Docking score: -10.574 kcal/mol

[167]

Glycyrrhizic acid (GlA) and theaflavin 3,3-digallate (TF3)

SARS-CoV-2 Mpro (6LU7) and ACE2 receptor (IR4L)

In silico using AutoDock Vina

Binding energy to 6LU7: GlA = − 9.3 and TF3 = − 10; and with 1R4L: GlA = − 9.6 and TF3 = − 8.3 kcal/mol

[276]

Theaflavin

SARS-CoV-2 RBD

In silico using SwissDock

Idock score − 7.95 kcal/mol

[277]

Pedunculagin, tercatain, and castalin

SARS-CoV-2 Mpro, catalytic dyad residues: Cys145 and His41 (6Y84)

In silico using MOE 09

S score: − 18.58; − 23.11; and − 14.04

[166]

Hypericin, Amentoflavone, terflavin

Hypericum perforatum L. and Terminalia chebula Retz. or T. catappa L

SARS-CoV-2 Mpro (6LU7)

In silico using AutoDock Vina

Binding energy: − 10.4, − 9.7 and − 9.7 kcal/mol

[164]

Eriodictyol-7-O-rutinoside, narirutin

Flavanone glycoside in lemon and sweet orange

SARS-CoV-2 RdRp protein sequence (YP_009725307.1)

In silico using AutoDock Vina

Binding energy: -9.9 and -9.7 kcal/mol

[164]

Cis-miyabenol C

Foeniculum vulgare Mill. (fennel)

SARS-CoV-2 human transmembrane serine protease 2 (TMPRSS2: sequence NP_001128571.1)

In silico using AutoDock Vina

Binding energy: -9.4 kcal/mol

[164]

Ellagic acid

Prunica granatum

SARS-CoV-2 Mpro (6LU7)

In silico using AutoDock Vina

Binding affinity and IC: − 8.4 kcal/mol and 0.7 μM

[193]

5,7,3′,4′-tetrahydroxy-2′-(3,3-dimethylallyl) isoflavone

Myricitrin

Methyl rosmarinate

Psorothamnus arborescens

Myrica cerifera

Hyptis atrorubens Poit

SARS-CoV-2 3CLpro (PMDB ID PM0082635)

In silico using MOE

Binding affinities:

− 29.57

− 22.13

− 20.62

[278]

Agathisflavone

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using AutoDock 4.1

Binding energy: − 8.4 kcal/mol

[173]

Albireodelphin

SARS-CoV-2 RdRp (pdb id: 6M71) and spike protein (pdb id: 6VW1)

In silico using AutoDock 4.1

Binding energy: − 9.8 and − 11.2 kcal/mol

[173]

Inophyllum G2

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using AutoDock Vina

Docking score: − 8.8 kcal/mol

[176]

Daphnorin

SARS-CoV-2 viral methyltransferase (nsp16/10 complex, pdb id: 6W4H) and RBD (pdb id: 6M0J)

In silico using AutoDock Vina

Docking scores: − 9.8 and − 8.2 kcal/mol

[176]

Isodispar B and daphnogirin

SARS-CoV-2 hACE2 (pdb id: 6VW1)

In silico using AutoDock Vina

Docking score: − 8.0 kcal/mol

[176]

Isorhamnetin-3-O-rutinoside (narcissin)

Salvadora persica L

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using AutoDock

Binding energy:− 8.2530 kcal/mol

[279]

Acetoside

(polyherbal formulation

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using iGEMDOCK

Binding energy: − 153.06 kcal/mol

[280]

Demethyloleuropein

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using AutoDock Vina

Binding energy: -8.90 kcal/mol

IC₅₀ prediction: 11.58 μM

[177]

Nuzhenide oleoside

SARS-CoV-2 S protein (pdb id: 6LZG)

In silico using AutoDock Vina

Binding energy: − 8.90 kcal/mol. IC₅₀ prediction: 6.44 μM

[177]

Myricitrin

Quercetin-3-O-glucuronide

Phyllanthus amarus

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using AutoDock Vina

Binding affinity: − 9.6 kcal/mol, and − 9.4 kcal/mol

[281]

Isorhamnetin-3-O-rutinoside (narcisin)

Salvadora persica

SARS-CoV-2 Mpro (pdb id: 6LU7)

In silico using AutoDock Vina

Docking score: − 8.2530 kcal/mol

[279]