A review on molecular docking analysis of phytocompounds against SARS-CoV-2 druggable targets

Figures & data

Figure 1. PRISMA flowchart showing all literature screened, included, and reviewed for this study.

Figure 2. An illustration of the genomic organization and structure of SARS-CoV-2. (A) Genomic organization of SARS-CoV-2. The ORF1a and ORF1b of the viral RNA genome encode 16 non-structural proteins (nsp1–nsp16). Nsp3 and nsp5 encode PL^pro and 3CL^pro, respectively, which are essential for viral replication and pathogenesis. The genomic organisation of S glycoprotein showing its two subunits (S1 and S1) is depicted below the viral genome. Dotted lines within this structure indicate the S1/S2 cleavage site. Other important components of the S glycoprotein such as signal protein (SP), receptor-binding domain (RBD), fusion peptide (FP), heptad repeat (HR1 and HR2), transmembrane domain (TM), and cytoplasm domain (CP) are depicted. (B) Structure of SARS-CoV-2 showing its single-stranded positive-sense RNA genome and essential structural proteins.

Table 1. List of 16 coronaviral non-structural proteins with their functions.

nsp	Function	References
nsp1	Degradation of mRNA and inhibition of IFN signals	Tanaka et al. 2012
nsp2	Essential for proofreading viral replication	(Harcourt et al. 2004; Naqvi et al. 2020)
nsp3	PL^pro: proteolytic processing of polyproteins, plays vital role in viral replication and host infection; blocking of host immune response	(Lei et al. 2018; Yu et al. 2020)
nsp4	Formation of DMV; may complex with nsp3 and nsp6	(Gadlage et al. 2010; Beachboard et al. 2015; Chan et al. 2020)
nsp5	3CL^pro: polypeptides cleaving, viral replication, and modulation of immune system – inhibition of IFN	(Zhou et al. 2019; Chen et al. 2020)
nsp6	Formation of DMV; restriction of autophagosome expansion; may complex with nsp3 and nsp4	(Angelini et al. 2013; Cottam et al. 2014; Chan et al. 2020)
nsp7	Complex with nsp8 and nsp12; may act as clamp for RdRp	(Zhai et al. 2005; Fehr and Perlman 2015; Kirchdoerfer and Ward 2019)
nsp8	Forms complex with nsp7 and nsp12; acts as a primase	(Zhai et al. 2005; te Velthius et al. 2012; Kirchdoerfer and Ward 2019)
nsp9	Dimerization, RNA binding, and interaction with nsp8	(Egloff et al. 2004; Sutton et al. 2004; Zeng, Deng et al. 2018)
nsp10	Interaction with ExoN domain (nsp14); scaffold protein for nsp14 and nsp16	(Chen et al. 2011; Decroly et al. 2011; Bouvet et al. 2014; Ma et al. 2015)
nsp11	Unknown	(Fang et al. 2008)
nsp12	RdRp: replication of viral RNA	(Ahn et al. 2012; Kirchdoerfer and Ward 2019; Lung et al. 2020)
nsp13	RNA helicase: unwinding of nucleic acid; 5′ triphosphatase	(Adedeji and Lazarus 2016; Hao et al. 2017; Jia et al. 2019)
nsp14	ExoN acts a proof-reader of viral genome; N7-MTase	(Graepel et al. 2017; Chen et al. 2020)
nsp15	EndoU: cleavage of viral polyuridine sequences, evasion of immune cells, attacks immune system	(Hackbart et al. 2020; Kim et al. 2020)
nsp16	2′-O-MTase: protects viral RNA from MDA5 recognition; negative regulation of host immunity	(Chen et al. 2011; Decroly et al. 2011; Shi et al. 2019)

Note: IFN: interferon, PL^pro: papain-like protease, DMV: double-membrane vesicle, 3CL^pro: chymotrypsin-like protease, RdRp: RNA-dependent RNA polymerase, ExoN: exoribonuclease, EndoU: endoribonuclease, 2′-O-MTase: 2′O-ribose methyltransferase.

Figure 3. Comparison of traditional and virtual methods of drug development.

Table 2. Compounds with potential against SARS-CoV-2 non-structural proteins evaluated through computational screening.

Compound	Type	Source	Target	Binding energy (kcal/mol)	Binding site(s)	Docking tool	Pharmacological evidence	References
(2S)-Eriodictyol 7-O-(6^″- Ogalloyl)-beta-D-glucopyranoside	Glycoside	Phyllanthus emblica	3CL^pro	−19.47	Thr24, Thr25, Gly143, Met49, Cys145, His41, Thr26, Cys44, Thr45, Glu166, Leu167, Gln189, Thr190, Ala191, Gln192	Software MOE	–	(ul Qamar et al. 2020)
10-Hydroxyusambarensine	Alkaloid	Strychnos usambarensis	3CL^pro	−10.0	Tyr54, Met49, Cys145, His163, Met165, Glu166, Pro168, Gln189	AutoDock vina 4.2	Antimalarial potential	(Gyebi et al. 2020)
22-Hydroxyhopan-3-one	Terpenoid	Cassia siamea	3CL^pro	−8.6	Lys137, Tyr239, Leu275, Leu286, Leu287	AutoDock vina 4.2	Antimicrobial potential	(Gyebi et al.2020)
3,5,7,3′,4′,5′-Hexahydroxy flavanone- 3-O-beta-D-glucopyranoside	Glycoside	Phaseolus vulgaris	3CL^pro	−19.10	Met49, Cys145, His41, Thr24, Thr25, Thr26, Cys44, Ser46, Asn142, His164, Met165, Glu166, Gln189	Software MOE	–	(ul Qamar et al. 2020)
5,7,3′,4′-Tetrahydroxy- 2′-(3,3-dimethylallyl) isoflavone	Phenolic	Psorothamnus arborescens	3CL^pro	−29.57	His41, Cys145, Thr24, Thr25, Thr26, Cys44, Thr45, Ser46, Met49, Asn142, Gly143, His164, Glu166, Gln189	Software MOE	Anti-leishmanial agent	(ul Qamar et al. 2020)
6-Oxoisoiguesterin	Terpenoid	Salacia spp.	3CL^pro	−9.1	His41, Met49, Cys145, Met165, Gln189	AutoDock vina 4.2	Antimicrobial potential	(Gyebi et al. 2020)
Amaranthin	Lectin	Amaranthus tricolour	3CL^pro	−18.14	Thr26, Glu166, Cys145, His41, Thr24, Thr25, Cys44, Cys44, Thr45, Asn142, His163, His164, Met165, Glu166, Leu167, Pro168, Gln189	Software MOE	–	(ul Qamar et al. 2020)
Andrographolide	Terpenoid	Andrographis paniculata	3CL^pro	−3.1	Gly143, Cys145, Glu166	Dock 6	Antiviral, anti-inflammatory, antidiabetic, anticancer activity	(Dai et al. 2018; Enmozhi et al. 2020)
Neoandrographolide	Terpenoid	Andrographis paniculata	3CL^pro, PL^pro, RdRp	−7.4 to −7.1	PLpro: Leu163, Gly164, Asp165, Tyr265, Tyr269, Gln270, Gly273, Tyr274; 3CLpro: Thr26, Ser47, Met50, Phe141, Leu142, Asn143, Gln190; RdRp: Tyr340, Asp337, Arg438, Asp508, Arg509. Ser644	AutoDock vina	Antiviral, anti-inflammatory, anticancer activity	(Murugan et al. 2020)
Anisofolin A	Phenolic	Leucas spp.	3CL^pro	−8.72	Leu4	SwissDock	Anti-mycobacterial, antimalarial activity	(Miyaichi et al. 2006; Mishra et al. 2020)
Apigenin	Phenolic	Allium sativum (garlic), Malus domestica (apple), Thymus vulgaris (thyme), Capsicum annuum (red pepper)	3CL^pro	−7.8	Met49, Ser144, Cys145, Glu166	AutoDock 4.2	Antiviral activity against hepatitis B virus, adenoviruses, African swine fever virus	(Zakaryan et al. 2017; Sampangi- Ramaiah et al. 2020)
Apigenin 7-glucoside	Phenolic	Thymus spp.	3CL^pro	−8.36	Gly71, Asn119	SwissDock	Anti-HIV activity	(Miyaichi et al. 2006; Mishra et al. 2020)
Apiin	Phenolic	Petroselinum crispum	3CL^pro	−8.7	His41, Ser46, Met165, Pro168, Gln189	SwissDock	Anti-inflammatory potential	(Das et al. 2020)
Arjunglucoside-I	Terpenoid	Terminalia chebula	3CL^pro	−7.9	Thr26, Leu27, Thr25, His41, Gly143, Phe140, Leu141, Asn142, Ser144, Cys145, His163, Met165, Glu166	AutoDock 4.2	Antioxidant, anti-inflammatory, antiplasmodial activity	(Umesh et al. 2020)
Baicalin	Phenolic	Scutellaria baicalensis (Chinese Skullcap)	3CL^pro	−8.1	Met49, Ser144, Cys145, Glu166, Pro168	AutoDock vina	Antiallergic, anti-inflammatory activity	(Islam et al. 2020)
Betulinic acid	Saponin	Betula spp.	3CL^pro	−4.23	Asn157, Tyr172, Gln175, Glu204	AutoDock 4	Anti-HIV, anti- inflammatory, anthelmintic, antimalarial property	(Dehelean et al. 2012; Zhang et al. 2016; Saeed et al. 2018; Zhang, Wu et al. 2020)
Calceolarioside B	Phenolic	Fraxinus sieboldiana	3CL^pro	−19.87	His41, Gly143, Cys145, Glu166, Thr24, Thr25, Thr26, Leu27, Ser46, Leu50, Leu141, Asn142, Ser144, His164, Met165, Gln189	Software MOE	Anti-respiratory syncytial viral activity	(Dong et al. 2017; ul Qamar et al. 2020)
Carnosol	Terpenoid	Rosmarinus officinalis (rosemary)	3CL^pro	−8.2	Thr26, Leu27, His41, Cys44, Met49, Cys145, His164, Glu166, Gln189, Met165, Arg188	AutoDock 4.2	Antioxidant, anti- inflammatory, antimicrobial anticancer activity	(Umesh et al. 2020)
Carvacrol	Phenolic	Origanum spp.	3CL^pro	−5.9	Leu27, His41, Met49, Asn142, Gly143, Cys145, Met165	AutoDock vina 4.2	Antiviral (HSV, retrovirus, respiratory syncytial virus), antimicrobial activity	(Marinelli et al. 2019; Kumar, Choudhir et al. 2020)
Cordifolin	Phenolic	Tinospora cordifolia	3CL^pro	−8.77	Leu4, Ser46, Asn142, Gln189	SwissDock	Anti-HIV protease activity	(Mishra et al. 2020)
Coriandrin	Furanocoumarin	Coriandrum sativum (coriander)	3CL^pro	−6.4	His41, Met49, Cys145, Met165, Gln189	AutoDock 4.2	Antiviral, anticancer property	(Sampangi-Ramaiah et al. 2020)
Coumaroyl tyramine	Phenolic	Physalis minima; Allium fistulosum	PL^pro, 3CL^pro	−4.18, −3.22	PLpro: Lys5, Gln127, Lys137, Glu290; 3CLpro: Pro108, Gln110, Thr111, Val202, Asp245, Ile249, Asp295	AutoDock 4	Antioxidant activity, inhibition of acetyl cholinesterase, cell proliferation	(Neelam et al. 2010; Zhang, Wu et al. 2020)
Cryptoquindoline	Alkaloid	Cryptolepis sanguinolenta	3CL^pro	−9.7	Met49, Cys148, Met165	AutoDock vina 4.2	Antimicrobial activity	(Gyebi et al. 2020)
Cryptotanshinone	Terpenoid	Salvia miltiorrhiza	PL^pro,3CL^pro	−5.25, −6.23	PLpro: Asn157, Tyr172; 3CLpro: Gln110, Asn151, Asp153, Asp295	AutoDock 4	Antimicrobial, antiparasitic, anti-inflammatory, anticancer activities	(Zeng, Fan et al. 2018; Zhang, Wu et al. 2020)
Curcumin	Phenolic	Curcuma longa (turmeric)	3CL^pro	−7.0	His41, Met49, Leu141, Gly143, Ser144, Cys145, Met165	AutoDock 4.2	Antioxidant, anti-inflammatory, antimicrobial, antiviral activity against dengue virus, HPV, HIV, Zika, chikungunya viruses	(Zakaryan et al. 2017; Kim et al. 2019; Sampangi-Ramaiah et al. 2020)
			3CL^pro	−8.2	Gly143, Cys145, Pro168, Gln192	SwissDock		(Das et al. 2020)
Desmethoxycurcumin	Phenolic	Curcuma longa (turmeric)	3CL^pro	−7.9	Met49, Cys44, Pro168	SwissDock	Anticancer, anti-inflammatory activity	(Das et al. 2020)
Desmethoxyreserpine	Alkaloid	Rauwolfia canescens	3CL^pro	−3.52	Val104, Arg105, Ile106, Gln110, Asn151, Asp153, Ile249	AutoDock 4	Antihypertensive activity	(Zhang, Wu et al. 2020)
Dihomo-γ-linolenic acid	Fatty acid	Borago officinalis	3CL^pro	−3.88	Gln107, Pro108, Gln110, Thr292, Pro293	AutoDock 4	Attenuation of atherosclerosis, anti-inflammatory property	(Wang et al. 2012; Gallagher et al. 2019; Zhang, Wu et al. 2020)
Epigallocatechin	Phenolic	Camellia sinensis	3CL^pro	−7.3	Thr26, His41, Asn142	SwissDock	Anti-inflammatory, anticancer, antioxidant potential	(Das et al. 2020)
Epigallocatechin gallate	Phenolic	Camellia sinensis	3CL^pro	−7.96	Phe140, Cys145, Glu166, Gln189, Gln192	SwissDock	Antioxidant, anti-inflammatory, anticancer potential	(Das et al. 2020)
Friedelin	Terpenoid	Clerodendrum spp.	3CL^pro, RdRp	−7.9, −7.1	Pro168, Asp623	AutoDock vina	Antimicrobial, anti- obesity, anticancer, anti-inflammatory activity	(Kar et al. 2020)
Glabridin	Phenolic	Glycyrrhiza glabra (liquorice)	3CL^pro	−8.0	Cys145, Pro168	AutoDock 4.2	Antioxidant potential	(Sampangi- Ramaiah et al. 2020)
			3CL^pro	−7.6	His41, Leu27, Cys145	SwissDock		(Das et al. 2020)
			3CL^pro	−8.1	His41, Met49, Met165, Glu166	AutoDock vina		(Islam et al. 2020)
Glucobrassicin	Glucosinolate	Brassica spp. (cabbage, broccoli, mustard)	3CL^pro	−8.1	His41, Leu141, Ser144, Met165, Gln189	AutoDock 4.2	–	(Sampangi- Ramaiah et al. 2020)
Glycycoumarin	Phenolic	Glycyrrhiza glabra (liquorice)	3CL^pro	−7.5	Leu141, Cys145, His163, Met165, Glu166	AutoDock 4.2	Antispasmodic activity	(Kim et al. 2019; Sampangi- Ramaiah et al. 2020)
Glycyrrhizin	Terpenoid	Glycyrrhiza glabra (liquorice)	3CL^pro	−7.8	His41, Met49, Cys145, Met165, Thr190	SwissDock	Antioxidant, anti-inflammatory property	(Das et al. 2020)
			3CL^pro	−7.2	Phe134, Pro184, Pro241	AutoDock 4.2		(Sampangi- Ramaiah et al. 2020)
Hederagenin	Terpenoid	Nigella sativa (black cumin), Luffa cylindrica (sponge gourd), Momordica dioica (spiny gourd)	3CL^pro	−7.6	Met49, Leu141, Ser144, Cys145	AutoDock 4.2	Antitumour potential	(Sampangi- Ramaiah et al. 2020)
Hesperidin	Phenolic	Citrus spp., Valeriana jatamansi	3CL^pro	−9.0	His4, Thr24, Thr25, Thr45, Ser46, Met49, Cys145	SwissDock	Anti-inflammatory, antioxidant, antitumour, antiviral activity	(Das et al. 2020)
Kaempferol	Phenolic	Spinach, kale	3CL^pro	−6.01	Arg105, Ile106, Gln110, Thr111, Asp295	AutoDock 4	Antimicrobial, antitumour, anti-inflammatory, antioxidant, antidiabetic, neuroprotective properties	(Imran et al. 2019; Zhang, Wu et al. 2020)
Leucoefdin	Phenolic	Musa spp. (banana)	3CL^pro	−9.29	Met49, Tyr54, Pro52, Phe140, Leu141, Cys145, His163, His164, Met165, Glu166	Glide	Antimicrobial, hypoglycaemic, antitumour property	(Singh and Mishra 2020)
Licoleafol	Phenolic	Glycyrrhiza uralensis	3CL^pro	−19.64	Cys145, His41, Thr24, Thr25, Thr26, Cys44, Thr45, Met49, Gly143, His163, His163, Met165, Glu166, Gln189	Software MOE	–	(ul Qamar et al. 2020)
Lignan	Phenolic	Grains, nuts, seeds, vegetables	3CL^pro	−4.27	Gln110, Asn151, Thr111, Thr292, Pro293, Asp295, Arg298	AutoDock 4	Antibacterial, antifungal activities	(Thirupathaiah et al. 2015; Zhang, Wu et al. 2020)
Liquiritigenin	Phenolic	Glycyrrhiza glabra (liquorice), Glycyrrhiza uralensis (Chinese liquorice)	3CL^pro	−7.7	Met49, Leu141, Gly143, Ser144, Cys145, His163, Met165, Asp187, Arg188	AutoDock 4.2	–	(Sampangi- Ramaiah et al. 2020)
Luteolin	Phenolic	Lonicera spp. (honeysuckle)	3CL^pro, PL^pro	−7.8 to −5.37	Gln189, Leu4, Asn142, Thr26, Asn180, Arg105, Phe185, Gln965, Ser968, Asn969, Tyr273, Leu270, Val-330	AutoDock vina	Antiviral activity against encephalitis virus, iridovirus	(Liu et al. 2020; Yu et al. 2020)
			3CL^pro	−8.35	Phe219	SwissDock		(Mishra et al. 2020)
Luteolin–4-glucoside		Derivative of luteolin	3CL^pro	−7.87	Glu240	SwissDock	Antioxidant activity	(Mishra et al. 2020)
Methyl rosmarinate	Phenylpropanoid	Hyptis atrorubens Poit	3CL^pro	−20.62	Cys145, His41, Thr24, Thr25, Thr26, Cys44, Thr45, Met49, Leu141, Asn142, Gly143, Ser144, His163, His164, Glu166, Gln189	Software MOE	Antidiabetic activity	(ul Qamar et al. 2020)
Moupinamide	Alkaloid	Piper nigru	PL^pro	−3.05	Asp77, Arg83, Ala154, Asm157, Gln175, Gln204	AutoDock 4	Antioxidant property	(Zhang, Wu et al. 2020)
Myricetin 3-O-beta-D-glucopyranoside	Glycoside	Camellia sinensis (green tea)	3CL^pro	−18.42	Asn142, Glu166, Cys145, His41, Thr24, Thr25, Thr26, Thr45, Ser46, Met49, Leu141, Gly143, Ser144, His163, His164, Met165, Gln189	Software MOE	Anti-inflammatory activity	(ul Qamar et al. 2020)
Myricitrin	Phenolic	Myrica cerifera	3CL^pro	−22.13	Gly143, Cys145, His41, Thr24, Thr25, Thr26, Leu27, Cys44, Ser46, Met49, Leu141, Asn142, Ser144, His163, Glu166, Gln189	Software MOE	Antiallergic, anti-inflammatory, antioxidant, antifibrotic activity	(ul Qamar et al. 2020)
			3CL^pro	−7.9	Thr24, Thr25, Thr26, Asn42, Asn119	SwissDock		(Das et al. 2020)
N-cis-feruloyl tyramine	Phenolic	Capsicum annuum	PL^pro3CL^pro,	−3.11, −4.31	PLpro: Asn157, Tyr172; 3CLpro: Val104, Arg105, Ile106, Gln110, Asn151, Thr292, Asp295	AutoDock 4	Anti-inflammatory potential	(Wishart et al. 2018; Zhang, Wu et al. 2020)
Oleanolic acid	Terpenoid	Thymus vulgaris (thyme), Rosmarinus officinalis (rosemary), Olea europaea (Clove)	3CL^pro	−6.0	Cys145, His163, Gln189	AutoDock vina 4.2	Antioxidant, anticancer, antidiabetic, antimicrobial, antihypertensive, anti-inflammatory property	(Jesus et al. 2015; Kumar, Choudhir et al. 2020)
			3CL^pro	−7.8	His41, Met49, Ser144, Cys145	AutoDock 4.2		(Ayeleso et al. 2017; Sampangi- Ramaiah et al. 2020)
Puerarin	Phenolic	Radix puerariae	3CL^pro	−8.4	His41, Cys44, Gly143, Glu166	SwissDock	Antioxidant, anti-inflammatory, hypoglycaemic, neuroprotective property	(Das et al. 2020)
Quercetin	Phenolic	Raphanus spp., Malus domestica, (apple) Foeniculum vulgare, Allium cepa (onion), Camellia sinensis (green tea)	PL^pro3CL^pro	−4.62, −6.25	PLpro: Tyr155, Ser171, Tyr172, Gln175, His176, Glu204; 3CLpro: Gln110, Thr111, Asn151, Ile249, Thr292, Asp295, Arg298	AutoDock 4	Anti-inflammatory, antithrombotic, antidiabetic, hepatoprotective, antioxidant, antiviral activity	(Zakaryan et al. 2017; Zhang, Wu et al. 2020)
			3CL^pro	−8.04	Arg105	SwissDock		(Mishra et al. 2020)
			3CL^pro	−7.3	Leu141, Gly143, Ser144, Cys145, His163, Met165, Arg188	AutoDock 4.2		(Zakaryan et al. 2017; Sampangi- Ramaiah et al. 2020)
Quercitrin	Phenolic	Allium cepa (onion)	3CL^pro	−8.3	Thr25, Thr45, Gly143, Glu166	SwissDock	Antioxidant, anti-inflammatory	(Das et al. 2020)
Rhoifolin	Phenolic	Rhus succedanea	3CL^pro	−8.4	His41, Cys44, Asn119, His145, Glu166	SwissDock	Antiretroviral potential	(Das et al. 2020)
Rosmanol	Terpenoid	Rosmarinus officinalis (rosemary)	3CL^pro	−8.0	Thr25, His41, Met49, Phe140, Leu141, Asn142, His143, Ser144, Glu166, Met165	AutoDock 4.2	Apoptosis induction	(Umesh et al. 2020)
Rosmarinic acid	Phenolic	Thymus vulgaris (thyme), Ocimum basilicum (basil), Rosmarinus officinalis (rosemary), Salvia officinalis (sage)	3CL^pro	−7.1	Lys102, Val104, Thr111, Asn151, Ser158, Phe294	AutoDock 4.2	Anti-inflammatory, antioxidant potential	(Sampangi- Ramaiah et al. 2020)
Rutin (quercetin-3-O- rutinoside)	Phenolic	Houttuynia cordata, Forsythia suspensa, Morus alba, Prunella vulgaris	3CL^pro	−9.6	His41, Leu141, Asn142, Cys145, Glu166, Thr190, Gln192	SwissDock	Antioxidant, antimicrobial, anti- inflammatory, antitumour activity	(Das et al. 2020)
			3CL^pro	−8.67	Thr26, Phe140, Leu141, Asn142, Ser144, Cys145, His163, Glu166, Gln189			(Hu et al. 2020)
Safficinolide	Terpenoid	Salvia officinalis (sage)	3CL^pro	−6.8	Val104, Gln110, Ser158, Phe294	AutoDock 4.2	Antiviral activity	(Sampangi- Ramaiah et al. 2020)
Sageone	Terpenoid	Salvia officinalis (sage)	3CL^pro	−7.1	His41, Cys145, His164, Met165	AutoDock 4.2	Antiviral property	(Sampangi- Ramaiah et al. 2020)
Scutellarin	Phenolic	Scutellaria baicalensis (Chinese Skullcap)	3CL^pro	−8.3	Thr26, Gly143, Cys145	SwissDock	Antioxidant, anti-inflammatory, vascular relaxation, anti-platelet, anticoagulation	(Das et al. 2020)
Stigmasterol	Terpenoid	Clerodendrum spp.	3CL^pro, RdRp	−7.7, −7.0	Pro168, Lys545, Arg555, Thr687, Ala688	AutoDock vina	Antioxidant potential	(Kar et al. 2020)
Sugiol	Terpenoid	Calocedrus formosana	3CL^pro	−6.04	Gln110, His246, Thr292, Pro293, Phe294, Asp295	AutoDock 4	Antioxidant, antiviral agent, anti-inflammatory antineoplastic property	(Kim et al. 2019; Zhang, Wu et al. 2020)
Tanshinone IIa	Terpenoid	Salvia miltiorrhiza	PL^pro3CL^pro	−5.02, −5.17	PLpro: Asp77, Arg83, Tyr155, An157, Tyr172, His176; 3CLpro: Gln110, Asn151, Asp153, Thr292 Pro293, Phe294	AutoDock 4	Cardioprotective; antioxidant, anti-inflammatory, antithromboticpotential	(Shang et al. 2012; Zhang, Wu et al. 2020)
Taraxerol	Terpenoid	Clerodendrum spp.	3CL^pro, RdRp	−8.4, −7.4	Glu166, Pro168, Ala191, Lys545, Arg555	AutoDock vina	Antimicrobial, anti-inflammatory, anti-obesity, anticancer property	(Kar et al. 2020)
Theaflavin	Phenolic	Camellia sinensis (green tea)	RdRp	−9.11	Asp452, Arg553, Arg624	idock & Blind docking	Broad-spectrum antiviral activity against influenza viruses, hepatitis C virus.	(Yang et al. 2014; Chowdhury et al. 2018; Lung et al. 2020)
Ursolic acid	Terpenoid	Malus domestica (apple), Thymus vulgaris (thyme), Rosmarinus officinalis (rosemary), Mentha piperita (peppermint)	3CL^pro^3	−4.0	Thr24, Thr25, Thr26, Cys44, Thr45, Ser46, Asn142, Gly143, Cys145, Glu166	AutoDock vina 4.2	Antiviral, antioxidant, antimicrobial, anticancer potential	(Jesus et al. 2015; Kumar, Choudhir et al. 2020)
			3CL^pro	−7.6	Val104, Thr111, Phe294	AutoDock 4.2		(Kim et al. 2019; Sampangi- Ramaiah et al. 2020)
Withanone	Lactone	Withania somnifera	3CL^pro	−4.42	Gln19, Thr24, Thr25, Thr26, His41, Cys44, Thr45, Ser46, Glu47, Met49, Pro52, Tyr54, Asn119, Asn142, Gly143, Ser144, Cys145, His164	Glide	Neuroprotective potential	(Kumar, Dhanjal et al. 2020)

Key: Catalytic residues of 3CL^pro are highlighted in bold; MOE: Molecular Operating Environment.

Table 3. Virtually screened phytocompounds with activity against SARS-CoV-2 structural proteins and host-associated proteins.

Compound	Type	Source	Target	Binding energy (kcal/mol) and docking tool	Binding site(s)	Pharmacological evidence	References
1,3,8-Trihydroxy-6-methylanthraquinone (emodin)	Phenolic	Rheum spp.	ACE2	−6.19 (ClusPro)	Ala71, Asp67, Lys74	Anti-inflammatory, anti-proliferative, anticarcinogenic property	(Basu et al. 2020)
24-Methylenecycloartan- 3-one	Terpenoid	Azadirachta indica	M protein	−10 (AutoDock vina)	Ile97, Phe100, Arg101, Ala104, Ser111, Phe112, Thr127, Ile128, Thr130, Arg158	Anticancer potential	(Borkotoky and Banerjee 2020)
24-Methylenecycloartanol	Terpenoid	Azadirachta indica	E protein	−10.8 (AutoDock vina)	Leu18, Leu19, Ala22, Phe23, Val25, Phe26, Val29	Antioxidant, anticancer property	(Kim et al. 2019; Borkotoky and Banerjee 2020)
7-Deacetyl-7- benzoylgedunin	Terpenoid	Azadirachta indica	E protein	−10.9 (AutoDock vina)	Ala15, Leu18, Leu19, Ala22, Val25, Phe26	Anticancer potential	(Kim et al. 2019; Borkotoky and Banerjee 2020)
Anthraquinone derivative	Phenolic	Oroxylum spp.	ACE2	−6.15 (ClusPro)	Ser105, Asn103, Gln102, Leu100, Phe28	Immunomodulatory, antiparasitic, antimicrobial, anticancer	(Basu et al. 2020)
Apigenin	Phenolic	Ocimum basilicum	Sgp	−7.7 (AutoDock vina)	Ser730, His1058, Ala1056, Ile870, Pro863, Leu861	Antiviral activity against hepatitis B virus, adenoviruses, African swine fever virus	(Zakaryan et al. 2017; Rane et al. 2020)
Baicalin	Phenolic	Scutellaria baicalensis (Chinese Skullcap)	ACE2	−8.46 (AutoDock vina)	Asn149, Arg273, His505	Antiallergic, anti-inflammatory activity	(Chen and Du 2020)
Beta-amyrin	Terpenoid	Azadirachta indica	M protein	−9.4 (AutoDock vina)	Ile97, Phe100, Arg101, Ala104, Ser111, Phe112, Ile128, Thr130	Antihyperglycemic, hypolipidemic potential	(Santos et al. 2012; Borkotoky and Banerjee 2020)
Chrysin	Phenolic	Oroxylum spp.	ACE2	−6.87 (ClusPro)	Thr129, Ile126, Thr125	Antioxidant, antispasmodic, anti-inflammatory	(Basu et al. 2020)
Curcumin	Phenolic	Curcuma longa (turmeric)	Sgp	−7.1 (AutoDock vina)	Thr430, Leu517, Ala520, Gln564, Phe565, Asn544, Leu546, Leu390, Val382	Antioxidant, anti- inflammatory, antimicrobial, antiviral activity against dengue virus, HPV, HIV, Zika, chikungunya virus	(Zakaryan et al. 2017; Rane et al. 2020)
Cycloeucalenone	Terpenoid	Azadirachta indica	E protein	−10.5 (AutoDock vina)	Ala15, Leu18, Leu19, Ala22, Phe23, Phe26, Val29	Cardioprotective, anticancer activity	(Kim et al. 2019; Borkotoky and Banerjee 2020)
Dihydrotanshinone	Terpenoid	Salvia miltiorrhiza	Sgp	−5.16 (AutoDock 4)	Gln954, Ala958, Thr961	Atherosclerosis attenuation	(Chaung et al. 2011; Zhang, Wu et al. 2020)
Dithymoquinone	Phenolic	Nigella sativa	S:ACE interface	−8.6 (AutoDock vina)	Phe28, Lys31, Glu35, Gln76, Leu79	Anticancer, antioxidant, anti-inflammatory property	(Ahmad et al. 2020)
Fisetin	Phenolic	Acacia spp.	Sgp	−8.5 (AutoDock vina)	Ile870, Pro880, Ser730, His1058, Thr732, Thr778	Antiviral activity against chikungunya Virus, HIV	Zakaryan et al. 2017; Rane et al. 2020
Friedelin	Terpenoid	Clerodendrum spp.	Sgp	−7.3 (AutoDock vina)	Tyr449, Asn450, Lys444	Antimicrobial, anti-obesity, anticancer, anti-inflammatory activity	(Kar et al. 2020)
Genistein	Phenolic	Genista tinctoria	Sgp	−8.2 (AutoDock vina)	Gly1059. Ser730, His1058, Thr732, Lys733, Pro863, Asn867, Thr870, Phe782, Ala1056	Angiogenesis inhibitor, phytoestrogenic, anticancer activity	(Zakaryan et al. 2017; Rane et al. 2020)
Glyasperin A	Phenolic	Glycyrrhiza glabra	Sgp	−7.9 (AutoDock 4)	Glu298, Phe318, Val320, Gln321, Thr323, Val595, Val620, Ile624	Antioxidant potential	(Sinha et al. 2020)
Glycyrrhizin	Terpenoid	Glycyrrhiza glabra¸ Glycyrrhiza radix	Sgp	−9.2 (AutoDock 4)	His625, Glu298, Arg319, Gln321, Val320, Gln321, Val320, Tyr343, The323, Ile624	Anti-inflammatory, anticancer, immunomodulating, neuroprotection, hepatoprotective property	(Kim et al. 2019; Sinha et al. 2020)
			ACE2	−9 (AutoDock vina)	Arg559, Gln388, Arg393, Asp30		(Chen and Du 2020)
Hesperidin	Phenolic	Citrus spp., Valeriana jatamansi	ACE2	−8.3 (AutoDock vina)	Tyr613, Ser611, Arg482, Glu479	Anti-inflammatory, antioxidant, antitumour, antiviral activity	(Chen and Du 2020)
			ACE2	−8.99 (ClusPro)	Asn63, Ala71, Lys74, Ser44		(Basu et al. 2020)
Isoliquiritin apioside	Phenolic	Glycyrrhiza glabra	Sgp	−7.4 (AutoDock 4)	Tyr612, Glu298, Phe318, Val320, Gln321, Val620, Ile624, His625	Anticancer potential	(Sinha et al. 2020)
Isorhamnetin	Phenolic	Tagetes lucida, pears	Sgp	−8.3 (AutoDock vina)	His1058, Val729, Ser730, Met731, Thr732, Lys733, Val860, Leu861, Pro863, Thr778, Ile870, Phe782, Ala1056	Antioxidant activity, anticancer, antimicrobial, anti- inflammatory	(Zakaryan et al. 2017; Rane et al. 2020)
Isothymol	Phenolic	Ammoides verticillata	ACE2	−5.8 (AutoDock vina 4.2)	Glu406, Lys441, Gln442, Thr445	Antimicrobial property	(Abdelli et al. 2020; Gyebi et al. 2020)
Kaempferol	Phenolic	Ficus benjamina, Rubus idaeus, Phaseolus vulgaris	Sgp	−7.4 (AutoDock vina)	Thr393, Ala522, Leu527, Cys391, Leu390, Asn544, Phe782, Ala1056	Antiviral activity against HCMV, HSV-1, HSV-2, influenza A virus	(Zakaryan et al. 2017; Rane et al. 2020)
Liquiritin	Phenolic	Glycyrrhiza glabra	Sgp	−7.7 (AutoDock 4)	His625, Val620, Gln321, Cys291, Gln321, Ile624, Val320	Antioxidant, antimicrobial, anti-inflammatory activity	(Sinha et al. 2020)
Luteolin	Phenolic	Ocimum basilicum, Petroselinum crispum, Capsicum annuum	Sgp	−8.2 (AutoDock vina)	Ala1056, Gly1059, His1058, Asp867, Ile870, Thr871, Pro863, Leu861, Lys733, Met731	Antiviral activity against HIV, Chikungunya virus, Japanese encephalitis virus, SARS-CoV, Rotavirus, Epstein–Barr virus	(Zakaryan et al. 2017; Rane et al. 2020)
Neoandrographolide	Terpenoid	Andrographis paniculata	S:ACE2 complex	−7.8 (Autodock vina)	Phe23, Ser27, Ser30, Asn34, Thr330, Ala331, Leu342	Antiviral, anti-inflammatory	(Murugan et al. 2020)
Nicotianamine	Metal chelator	Glycine max	ACE2	−5.1 (AutoDock vina)	Arg518, Glu406, Ser409, Gln522, Gln442	Metal translocation	(Chen and Du 2020)
Nimbolin A	Styrene	Azadirachta indica	E & M proteins	−11.2, −9.4 (AutoDock vina)	Asn15, Leu18, Leu19, Ala22, Phe23, Val25, Phe26, Trp31, Ile32, Leu35, Gln36, Phe37, Ala38, Asn41, Arg42, Phe45, Ala81, Ile82, Ala85, Asn203, Tyr204, Leu206, Thr208, Asp209	–	(Borkotoky and Banerjee 2020)
Nimocin	–	Azadirachta indica	E & M proteins	−11, −10.2 (AutoDock vina)	Leu18, Leu19, Ala22, Phe23, Val25, Phe26, Gln36, Ala38, Asn41, Arg42, Phe45, Gly78, Ala81, Ile201, Gly202, Asn203, Tyr204, Asp209	–	(Borkotoky and Banerjee 2020)
Phytosterol	Phenolic	Azadirachta indica	M protein	−9.5 (AutoDock vina)	Ile97, Phe100, Arg101, Ala104, Ser111, Thr127, Ile128, Thr130, Arg158	Hypocholesterolemic, antioxidant activity	(Yoshida and Niki 2003; Borkotoky and Banerjee 2020)
Piceatannol	Phenolic	Rheum palmatum, Euphorbia lagascae	S:ACE complex	−8.2 (AutoDock vina)	Asn33, His34, Glu37, Pro389, Lys403, Ser494, Tyr495, Gly496, Tyr505	Antioxidant, anticancer	(Wahebi et al. 2020)
Pterostilbene	Phenolic	Vaccinium spp., Pterocarpus marsupium	Sgp	−6.7 (AutoDock vina)	Thr393, Ala522, Ala520, His519, Asn544, Gln564, Leu390, Gly545, Phe543, Leu546, Phe565	Antiviral activity against HSV, HPV, influenza virus	(Zakaryan et al. 2017; Rane et al. 2020)
			S:ACE complex	−7.0 (AutoDock vina)	Asn33, His34, Glu37, Phe390, Ser496, Tyr505		(Wahebi et al. 2020)
Quercetin	Phenolic	Raphanus spp., Foeniculum vulgare, Capsicum annuum	Sgp	−8.5 (AutoDock vina)	Ser730, Met730, Met731, Lys733, Val 860, Leu861, Pro863, Ile870, Asp867, Ala1056, Pro1057, Gly1059, His1058	Anti-inflammatory, antithrombotic, antidiabetic, hepatoprotective, antioxidant, antiviral activity	(Zakaryan et al. 2017; Rane et al. 2020)
Resveratrol	Phenolic	Vaccinium spp.	Sgp	−7.9 (AutoDock vina)	Thr732, His1058, Lys733, Leu861, Pro863, Asp867, Ile870, Phe782	Antioxidant, anticancer, Antiviral activity against HIV-1, pseudorabies, MERS-CoV	(Zakaryan et al. 2017; Rane et al. 2020)
			S:ACE complex	−8.0 (AutoDock vina)	Asn33, His34, Glu37, Lys403, Lys353, Pro389, Tyr495, Gly496		(Wahebi et al. 2020)
Scutellarin	Phenolic	Scutellaria baicalensis (Chinese Skullcap)	ACE2	−14.9 (AutoDock vina)	Glu495, Arg482	Antioxidant, anti-inflammatory, vascular relaxation, anti-platelet, anticoagulation	(Chen and Du 2020)
Stigmasterol	Terpenoid	Clerodendrum spp.	Sgp	−7.2 (AutoDock vina)	Tyr449, Phe490	Antioxidant potential	(Kar et al. 2020)
Taraxerol	Terpenoid	Clerodendrum spp.	Sgp	−7.5 (AutoDock vina)	Leu455, Glu484, Tyr489	Antimicrobial, anti-inflammatory, anti-obesity, anticancer property	(Kar et al. 2020)

Note: Sgp: Spike glycoprotein, ACE2: Angiotensin-converting enzyme 2, M: membrane protein, E: envelop protein.

Figure 4. Interaction of representatives of phytoligands, quercetin, and tryptanthrin with SARS-CoV-2 3CL^pro and PL^pro, respectively (Mani et al. 2020) (Reuse permission was obtained from Elsevier, Licence number: 5034780990710).

Figure 5. The life cycle of SARS-CoV-2 and potential druggable targets of representative phytocompounds. Quercetin and luteolin predictably interact with 3CL^pro, PL^pro, and S glycoprotein, while neoandrographolide acts against 3CL^pro, PL^pro, host ACE2 receptor, RdRp and may also inhibit RNA replication.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.