1 s2.0 S0882401022001255 Main

Microbial Pathogenesis 168 (2022) 105512
Contents lists available at ScienceDirect
Microbial Pathogenesis
journal homepage: www.elsevier.com/locate/micpath
Multifaceted roles of plant derived small molecule inhibitors on replication

cycle of SARS-CoV-2
B. Uma Reddy a, *, 1, Nanda Kishore Routhu b, Anuj Kumar c, 1, **
a
Department of Studies in Botany, Vijayanagara Sri Krishnadevaraya University, Ballari, 583105, India
b
Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA
c
Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS UMR 5286, Lyon, 69008, France
A R T I C L E I N F O A B S T R A C T
Keywords: Introduction: Coronavirus disease 2019 (COVID-19) is an illness caused by the new coronavirus severe acute
SARS-CoV-2 respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has affected public health and the economy globally.
COVID-19 Currently approved vaccines and other drug candidates could be associated with several drawbacks which urges
Viral replication cycle
developing alternative therapeutic approaches.
Plants
Small molecule inhibitors
Aim: To provide a comprehensive review of anti-SARS-CoV-2 activities of plants and their bioactive compounds.
Antiviral therapeutics Methods: Information was gathered from diverse bibliographic platforms such as PubMed, Google Scholar, and
ClinicalTrials.gov registry.
Results: The present review highlights the potential roles of crude extracts of plants as well as plant-derived small
molecules in inhibiting SARS-CoV-2 infection by targeting viral or host factors essential for viral entry, poly
protein processing, replication, assembly and release. Their anti-inflammatory and antioxidant properties as well
as plant-based therapies that are under development in the clinical trial phases-1 to 3 are also covered.
Conclusion: This knowledge could further help understanding SARS-CoV-2 infection and anti-viral mechanisms of
plant-based therapeutics.
infected COVID-19 patients resulting in the unrecognized source of

medication errors and negative effects [2]. Therefore, it is essential to
1. Introduction
use an alternative and safer approach, such as plant-derived compounds.
Numerous scientific reports have documented the ability of plants
A newly emerged pandemic of COVID-19, caused by an infectious
and their secondary metabolites against SARS-CoV [91]. Despite being
coronavirus SARS-CoV-2, has severely affected the entire world and
new virus, there are multiple in-silico studies suggesting anti-SARS-
remains a health threat. The emergence of new strains that evade im
CoV-2 capability of plant-based small compounds. Additionally, in-vi
mune responses generated by the vaccines suggests an urgent need for
tro, cell culture and in-vivo clinical trials further validate and strengthen
developing alternative therapeutic approaches to cut down the COVID-
their COVID-19 suppressing potential.
19 infection rate and related morbidity and mortalities.
COVID-19 is currently being treated with several plausible drugs
2. Scope of the review
including antimalarial drugs [28], antiviral drugs [83], certain immu
nosuppressors [70], and convalescent plasma therapy. However, these
This review article aims to collect data on anti-SARS-CoV-2 activity
kinds of treatments are associated with several concerns, especially in
and therapeutic potential of natural plant extracts and phytocompounds
patients with severe disease conditions [90]. For example, severe
primarily based on in-silico (molecular docking and molecular dynamics)
adverse effects such as renal impairment and hypotension were
studies. An attempt has also been made to highlight in-vitro, cell culture,
observed in critically ill patients receiving remdesivir therapy [30].
in-vivo and clinical trial (phase 1 to 3) studies. Several bibliographic
Additionally, several case studies have reported that these standard
platforms such as PubMed, Science-Direct, Google Scholar, and
drugs exhibit drug-drug or nutrition-drug interactions into the severely
* Corresponding author.
** Corresponding author.
E-mail addresses: umareddy@vskub.ac.in (B. Uma Reddy), nanda.kishore.routhu@emory.edu (N.K. Routhu), anuj.kumar@inserm.fr (A. Kumar).
1
Equal corresponding authors
https://doi.org/10.1016/j.micpath.2022.105512
Received 18 January 2022; Received in revised form 27 March 2022; Accepted 30 March 2022
Available online 2 April 2022
0882-4010/© 2022 Elsevier Ltd. All rights reserved.
B. Uma Reddy et al. Microbial Pathogenesis 168 (2022) 105512
Abbreviations gRNA genomic RNA

ERGIC endoplasmic reticulum-Golgi intermediate complex
RBD receptor-binding domain LDLRA low density lipoprotein receptor class A
RBM receptor-binding motif SRDR scavenger receptor cysteine-rich domain
aa amino acids RdRp RNA dependent RNA polymerase
nsp non-structural protein kb kilobases
E envelope protein PLpro papain-like protease
M membrane protein 3-CLpro 3 chymotrypsin-like protease
N nucleocapsid EGCG Epigallocatechin 3-gallate
NTD N-terminal domain TF theaflavin
CTD C-terminal domain SF-1 superfamily-1
ACE2 angiotensin-converting enzyme 2 ADMET absorption, digestion, metabolism, excretion, and toxicity
TMPRSS2 transmembrane protease serine 2 QGRG Quercetin 3-glucosyl rhamnosyl galactoside
RNA ribonucleic acid 2′ -O-MTase 2′ -O- methyltransferase
sgRNAs sub-genomic RNAs kDa kilodalton
Fig. 1. Structure of the SARS-CoV-2 virus: Spike (S) is the surface glycoprotein that mediates the interaction of SARS-CoV-2 with the cell surface receptor
angiotensin-converting enzyme 2 (ACE2). The membrane glycoprotein (M) and envelope (E) are embedded in the host cell-derived lipid membrane which encap
sulates the viral nucleocapsid.
Fig. 2. Genome organization of SARS-CoV-2. Approximately 30 kb long viral genome comprises 10 open reading frames (ORFs) encoding 27 viral proteins. The
ORF1ab encompasses about 67% of the total viral genome and encodes 16 non-structural proteins (nsps). Whereas the accessory and structural proteins are encoded
by the remaining ORFs(adapted from Kim et al., 2020[116] with some modifications)
2
Fig. 3. The life cycle of SARS-CoV-2 and

potential targets of plant-derived small
molecule inhibitors (A-B) SARS-CoV- 2
spike protein binding to ACE2 followed by
internalization of the virus (C) uncoating of
the viral genome and its release into the
cytoplasm (D-E) translation of replicase
proteins (ORF1a/ab) followed by proteolysis
(F–K) Replication/transcription of the viral
genome. Incoming positive-strand genome
generates full-length negative-strand RNA
and sub-genomic RNA (sgRNAs). sgRNA
translation results in both structural proteins
and accessory proteins. (L–P) Structural
proteins S (spike), M (membrane), E (enve
lope), and viral nucleocapsid complex get
inserted into the ER-Golgi intermediate
compartment (ERGIC) for virion assembly
and release. Plant-based inhibitors (high
lighted in yellow boxes) can target the ma
jority of these steps as marked in red. (For
interpretation of the references to colour in
this figure legend, the reader is referred to
the Web version of this article.) (adapted
from de Vries 2020 [117] with some
modifications)
Fig. 4. Spike, ACE2, TMPRSS2 and Furin are the targets of viral entry inhibition. Plant-based inhibitors utilize several mechanisms to block SARS-CoV-2 entry.
ClinicalTrials.gov registry were used to gather research findings and to which requires TMPRSS2 proteolytic activity [9]. It is followed by
summarize them methodically as a review. uncoating of its genome and release into the host cell cytoplasm, which
undergoes translation to produce viral proteins. Non-structural proteins
3. Fundamentals of SARS-CoV-2 genome organization and life (NSPs) 2–16 contain RNA synthesis, proof reading, cofactor and host
cycle immune evasion activities [76,88]. A negative-sense RNA intermediate
is generated for the synthesis of positive-sense strand genomic RNA
SARS-CoV-2 infects human lung epithelial cells by binding to the cell (gRNA) as well as a set of shorter sub-genomic RNAs (sgRNAs). Finally,
surface located angiotensin-converting enzyme 2 (ACE2) receptor with the gRNA is packaged and assembled into progeny virions at the endo
the help of the receptor-binding domain (RBD) of spike protein (S pro plasmic reticulum-Golgi intermediate compartment (ERGIC). The
tein). The transmembrane serine protease 2 (TMPRSS2) is required for sgRNAs encode structural proteins such as envelope (E), membrane (M),
the priming/activation of the S-protein [35]. A high expression of ACE2 and nucleocapsid (N) and several accessory proteins (ORF3a, ORF6,
and TMPRSS2 in the gastrointestinal tract has been reported to be ORF7a, ORF7b, ORF8, and other ORFs) [9,59,68,74]. (Figs. 1–3).
associated with gastrointestinal symptoms seen in COVID-19 patients.
There are also a few studies describing changes in the gut microbiome of 4. Virus-host interactions: Potential antiviral targets
these patients compared to healthy persons [32].
More recently, it has been found that the cleavage of a multibasic site The virus-host interactions during the virus entry, replication, and
present between two subunits (S1 and S2) of S protein by furin protease pathogenesis play a crucial role in the virus life cycle. Several viral and
is also involved in S-protein mediated efficient membrane fusion, viral cellular factors facilitate this process in a coordinated manner. In SARS-
entry and the transmission of SARS-CoV-2 [36,65]. The virus is inter CoV-2 infection, the viral spike protein interaction with host ACE2,
nalized via directly through RBD- ACE2 interaction or membrane fusion TMPRSS2, and furin facilitate virus entry, which are thepotential drug
3
Fig. 5. Molecular structure of spike pro

tein of SARS-CoV-2 and interactions with
plant-based drugs. A furin cleavage site is
present at the interface between S1 and S2
subunits of the spike protein. Amino acid
positions of spike protein that can be inter
acted by different groups of plant-based in
hibitors (steroids, quinones, terpenoids,
flavonoids, and tannins) are also shown.
Please refer Table-1 for precise details. SP-
signal peptide; RBD- Receptor binding
domain; RBM- Receptor binding motif; TM-
transmembrane motif; FP- fusion peptide;
HR1-Heptad repeat-1, HR2-heptad repeat-2;
NTD- N-terminal domain, CP- cytoplasmic
domain(adapted from Joshi et al., 2020[40]
with some modifications).
Fig. 6. Molecular organization of host ACE-2 monomer showing the interaction sites of different classes of phytocompounds (quinones, alkaloids, flavonoids,
tannins, terpenoids, and organosulphur compounds) on the HEMGH/SARS CoV-2 spike protein binding domain and the collectrin domain (adapted from Bian and Li,
2021[118]).
targets for developing SARS-CoV-2 antivirals (Figure-4) and are dis efficiency, and higher number of amino acid interactions with spike
cussed below in detail. protein than synthetic hydroxychloroquine [53]). Another study showed
that daturaolone, gallotannins, taraxerol, tinosporide, withanolide-A,
4.1. Spike (S) protein deoxytubulosine, withametelin form strong hydrogen and
non-bonding interactions with the amino acids of spike protein (between
Spike is a trimeric glycoprotein that mediates the binding of the virus Arg 403 to Tyr 505) and have drug-likeliness properties based on Lip
to host cell surface-specific receptors and virus-cell membrane fusion inski’s rule of five. Moreover, these bioactive compounds have lower
[122]. It plays a vital role in determining host tropism and the diversity toxic effects and better gastrointestinal absorption than standards [56].
of coronaviruses (CoVs). SARS-CoV-2 is more contagious than SARS-CoV A simulation study using the crystal structure of SARS-CoV-2 S protein
as SARS-CoV-2 spike protein interacts with ACE2 with 10–20 folds demonstrated that saikosaponin-U and saikosaponin-V, oleanane de
higher affinity than SARS-CoV. The receptor-binding motif (RBM) rivatives found in Chinese medicinal plants, can also interact with the
(437–508 amino acids) present in the RBD (319–541 amino acids) of the spike glycoprotein via their octadecahydropicene and oxane rings [75].
S1 subunit (13–685 amino acids) of the spike protein is majorly Using molecular docking and conceptual density functional theory ap
responsible for the binding of the virus to ACE2 [7,8,89] (Figure-5). proaches, Kulkarni et al. showed that components of essential oils
In-silico docking results showed that the phytocompounds enlisted under (monoterpenes, terpenoid phenols and phenyl propanoids) have the
the spike section in Table-1 interact well with the hot-spot residues of potential to interact with the RBD [47]. The phytocompounds punica
the RBD of spike glycoprotein of SARS-CoV-2. lagin and punicalin (from Pomegranate), tenufolin, cinnamtannin-B1,
pavetannin-C1, 6-glucopyranosyl procyanidin B1, procyanidin-B7,
4.2. Angiotensin-Converting Enzyme 2 (ACE2) proanthocyanidin-A2 and Kaempferol-3-alpha-L-arabinoside-7-rhamno
side (from Cinnamon), frieldlin, and stigmasterol (from Clerodendrum
ACE2 is a single-pass type-1 transmembrane protein of 805 amino spp) were also found to be effective candidates exhibiting important
acids with an extracellular N-terminal peptidase domain and an intra interactions with the targeted S protein [41,66,79], suggesting that they
cellular C-terminus collectrin-like domain (CLD) [23]. The N- terminus could serve as possible candidates for further in-vitro and in-vivo evalu
has a zinc metallopeptidase binding motif (374–378 amino acids, ations. Additionally, a molecular dynamics simulation study of the
HEMGH) essential for the interaction with SARS-CoV-2 S-protein complex of RBD of S-protein with taraxerol for a time scale of 40 ns
(Figure - 6). Histochemical and single-cell RNA sequencing techniques revealed its potent anti-SARS-CoV-2 activity [41]. Tellimagrandin-II and
revealed that ACE2 is primarily expressed in type-II lung alveolar O-demethyl-deoxy curcumin isolated from plants used in Indian tradi
epithelial cells [33,95]. tional medicine demonstrated stable intramolecular interactions with
A recent study, using bioinformatics, cheminformatics, and molec Asn343, which could be an important hit to affect host-immune evasion
ular docking, has demonstrated that tea flavonoids (epigallocatechin by inhibiting S-protein glycosylation [85].
gallate, EGCG, and theaflavin gallate) have higher atomic contact en The complex between viral S protein and human ACE2 has also been
ergy value, dissociation constant (Ki)-value, surface area, ligand explored to identify antiviral phytochemicals. Using molecular
4
Fig. 7. Molecular structure of transmembrane protease serine-2 (TMPRSS2) and the interaction sites of tannins, steroidal lactone, and caffeate ester in its
domains. H-296, D-345 and S-441 are the catalytic residues present in the serine protease domain (adapted from Paoloni-Giacobino et al, 1997 [63] and Mahmoud
and Jarrar, 2021[119])
dynamics, hesperidin, a major flavonoid present in citrus fruits, has been domain (255–492 amino acids) [63] (Figure-7). For priming of the viral
demonstrated to interact with this complex noncompetitively at a site spike protein, TMPRSS2 cleaves off the spike protein at two sites,
different from that of S-protein. Further, the antiviral activity of hes Arg-685/Ser-686 and Arg-815/Ser-816. The catalytic site of TMPRSS2
peridin was validated by a quantitative structure-activity relationship consists of amino acid residues Ser-441, His-296, and Asp-345, whereas
study [12]. Another study, using virtual screening followed by the substrate-binding sites include Asp-435, Ser-460, and Gly-462 [34].
protein-ligand interaction approach, showed that phytochemicals like Molecular docking studies showed that the bioactive constituents of
glycyrrhizinic acid, maslinic acid, ursolic acid, corosolic acid, 2-hydrox different plants enlisted under the TMPRSS2 section in Table-1 and
yseneganolide, gedunin, and oleanane can bind firmly with the active presented in Figure-7 display significant interactions with the amino
site and other important amino residues of S protein and ACE2 through acid residues of the serine protease domain (255–492), particularly with
multiple noncovalent interactions [87]. Of particular interest, His-34 is the amino acids of catalytic and substrate binding sites.
an important amino acid of ACE2 receptor as it lies on the surface and The phytocompounds withaferin-A, withanolide-N, punicalin, puni
exhibits crucial interactions with the S protein. One of the molecular calagin, ellagic acid and gallic acid could interact well with the impor
dynamic studies revealed that the andrographolide and pterostilbene tant amino acid residues of TMPRSS2 [49,79]. Withanolide-N not only
could negatively affect SARS-CoV-2 by interacting with the His-34 [10]. showed stronger interactions compared to withaferin-A, but it could also
Rilapladib, a quinoline, can interrupt the spike-ACE2 complex [11]. downregulate the expression of TMPRSS2 mRNA in human breast can
Natural compounds such as isothymol, thymol, p-cymene, limonene, cer cell line. This observation led authors to predict its dual role in
and gamma-terpinene (from Ammoides verticillata), and 17- organosulfur inhibiting SARS-CoV-2 entry. The disruption of substrate binding was
compounds (from garlic) were also found to be potential inhibitors of most likely due to interactions of withanolide-N with the Ser-441 [49].
ACE2 receptor [1,82]. Further, xanthones, proanthocyanidins, secoir
idoids, naringenin, hesperetin, baicalin and neohesperidin, scutellarin, 4.4. Furin
nicotinamin, and glycyrinodin could exhibit ACE2 inhibition activity
[58]. Hesperidin can modulate the binding energy of ACE2-spike protein Furin is a subtilisin-like proprotein convertase located in the trans-
complex and affects the stability of viral-host interaction [12]. At the Golgi network. It cleaves a precursor protein with a specific amino acid
binding contact of the spike-ACE2 complex, the di-hydroflavone moiety pattern (Arg-X-X-Arg). The furin-like cleavage site, a 12-nt insertion at
of hesperidin has been predicted to be parallel to the β-6 sheet of RBD S1/S2 junction in the spike coding sequence, is absent in other members
[92]. Apart from this, punicalin and punicalagin from pomegranate peel of the same clade [13,19]. Furin cleavage site enhances receptor affinity
are predicted to interact with ACE2 and block entry of SARS-CoV-2 into and facilitates membrane fusion. The cleavage of this site occurs via
host cells [79]. Several bioactive compounds shown in research article priming of S protein which could provide a gain-of-function benefit to
by Mondal et al can interact with hot-spot binding residues (Lys31 and the SARS-CoV-2 for an efficient human to human transmission
Lys353) of the ACE2 receptor through hydrogen bond or non-bonded compared to other members of beta coronaviruses [13,19,54]. In-silico
interactions [56]. Besides these, geranium and lemon essential oils analyses suggested that punicalagin, punicalin, ellagic acid and gallic
downregulate the expression of ACE2 in human colon adenocarcinoma acid from pomegranate could interact with the active site residues and
cells as observed by western blot experiments [48]. More details of other crucial amino acid residues of furin (Table-1) and form more
in-silico studies, including types of interactions, binding energy values, stable complexes than sulconazole (control) [80]).
as well as identity and position of interacting amino acids with different
phytocompounds are presented in Table-1. 5. SARS CoV-2 replication inhibitors
The replication and transcription of the SARS-CoV-2 RNA genome (~

4.3. Transmembrane Serine Protease-2 30 kb) is catalyzed by an RNA-dependent RNA polymerase (RdRp)
domain located at the C-terminus of non-structural protein 12 (nsp12) in
Human TMPRSS2 is a 492 amino acid type-II transmembrane protein association with other non-structural proteins such as nsp3 (papain-like
that belongs to the serine protease family. The N-terminal half consists protease), nsp5 (3-chymotrypsin-like protease), nsp15 (endor
of a predicted transmembrane domain (84–106 amino acids), a low- ibonuclease) and nsp16 (2-O’ MTase).
density lipoprotein receptor class A domain (LDLRA, 113–148 amino
acids), and a scavenger receptor cysteine-rich domain (SRCR, 149–242
amino acids), whereas the C-terminus half contains a serine protease
Fig. 8. Location of amino acid interaction site (89–264) of tannins and flavonoids on SARS-CoV-2 nsp3 papain-like protease monomer(adapted from Joshi
et al., 2020 [40]).
5
Table 1
Interactions of plant-based small molecules with targeted SARS-CoV-2 or host proteins.
Spike Glycoprotein (viral protein)
Class Small molecule inhibitors Interacting amino acids with different classes of References
phytocompounds
Tannins Punicalin (3-IR and − 7.406 BE), punicalagin (6-IR and − 7.312 BE), Phe40, Leu95, Gln102, Asn103, Lys187, Asp206, Val209, [56,66,79].
Pedunculagin (4-HB, 6 NBI and − 7.7 BE), punigluconin (7-HB, 5- Asn210, Leu335, Phe342, Asn343, Pro346, Thr347, Trp349,
NBI and − 7.9 BE), chebulagic acid (5-HB, 5-NBI and − 7.5 BE), Val367, Leu368, Tyr369, Asn370, Ser371, Ala372, Phe374,
chebulinic acid (5-HB, 7-NBI and − 6.5 BE), cinnamtannin-B1 (3- Phe377, Asp382, Phe390, Arg393, Asn394, Glu398, Gln493,
HB, 3-HP and − 10.2 BE), 6-Glucopyranosyl procyanidin-B1 (8-HB, Ala396, His401, Glu402, Arg403, Glu406, Gln409, Lys417,
1-EI and − 9.9 BE), Procyanidin-B7 (2-HB, 3-HP, 2-EI and − 9.6 BE), Tyr449, Tyr453, Leu455, Phe456, Tyr489, Phe490, Leu492,
proanthocyanidin-A2 (5-HxB, 1-HP, 2-EI and − 9.4 BE), ellagic acid Gln493, Ser494, Tyr495, Gln496, Asn501, Tyr505, Asp509,
(3 IR and − 6.114 BE), gallic acid (2 IR and − 4.808 BE), gallotannins Arg514, Tyr515, Lys562, Lys562, Pro565
(6 HB, 7-NBI, − 7.4 BE).
Terpenoids Geraniol (2-HB and-5.0 BE), L-4-terpineol (2-HB and − 5.1 BE), Leu73, Asp350, Tyr385, Phe390, Asn394, Arg403, Asp405, [47,56,66]
carvacrol (1-HB and − 5.2 BE), limonene (12-HPI and − 5.1 BE), Glu406, Arg408, Gln409, Gly416, Lys417, Tyr449, Tyr451,
thymol (-5.4 BE), tinosporide (2HB, 6-NBI and − 6.4 BE), taraxerol Leu452, Tyr453, Leu455, Phe-456, Lys458, Ser-459, Leu461,
(7-NBI and − 7.9 BE), daturaolone (8 NBI and − 7.5 BE), glycyrrhizin Ile468, Thr470, Ile472, Glu484, Tyr489, Phe490, Pro491,
(7-HB, 3-NBI, − 7.1 BE), friedelin (1-HB, 2-IR and − 7.3 BE), Leu492, Gln493, Ser494, Tyr495, Gly496, Asn501, Tyr505
tenuifolin (4-HB, 2-HP and − 8.7 BE), ϒ-terpinene (− 4.8 BE),
α-terpinene (− 5.0 BE), camphene (2-HPI and − 5.2 BE), camphor (2-
HPI and − 4.8 BE).
Flavonoids Pavetannin-C1 (9-HB, 4-HP, 1-EI and − 11.1 BE), hesperidin (5 IR Ser44, Leu48, Ala292,Cys301, Leu303, Ile312, Tyr313, [12,47,56,57,
and − 8.99), chrysin (9 IR and − 6.87), querceitin 3-O- Thr315, Asn317, Phe318, Arg319, His345, Thr347, Ala348, 25,66]
robinobioside (5-HB, 6-NBI, − 7.9 BE), kaempferol 3 - alpha-L- Trp349, Asp350, His374, Glu375, His378, Asp382, Tyr385,
arabinofuranoside 7-rhamnoside (7-HB, 2-HP and − 8.7 BE), Gly395, Asn397, Glu398, His401, Arg403, Glu406, Tyr410,
catechin gallate (5 HB, 3 HP and − 6.1 BE), cinnamaldehyde (2-HB Lys417, Arg443, Ser448, Asn449, Tyr453, Arg454, Leu455,
and − 5.0 BE), Anthranol (1 HB, 2 HP and-9.08 BE),Apigenin (5 HB, 2 Phe456, Ser459, Glu471, Val472, Glu473, Gly474, Phe475,
HP and -10.09 BE)Derrisin (2 HB, 2 HP and -11.04 BE)Jaceidin (2 HB, Phe486, Tyr484, Thr487, Asn488, Ser494, Tyr495, Gly496,
2 HP and -10.54 BE),Lupiwighteone (1 HB, 3 HP and -9.92 BE), Phe497, Tyr505, Tyr510, Arg514, Tyr515, Gln516, Leu517,
Luteolin (2 HB, 2 HP and -10.92 BE), Mundulinol (2 HB, 1 HP and His519, Ala520, Ala522, Asn544, Gly545, Leu546, Val595,
-11.08 BE), Naringenin (2 HB, 2 HP and -10.12 BE), Rhamnetin (2 HB, Pro665, Ser730, Met731, Lys733, Gln762, Arg765, Ala766,
2 HP and -10.15 BE), Tamarixetin (2 HB, 1 HP and -10.33 BE), Asn856, Val860, Pro863, Asp867, Asp867, Lys964, Leu966,
Cannflavin (1 HB, 2 HP and -9.11 BE), Methylglovanon (1 HB, 1 HP Ser967, Phe970, Asn969, His1058.
and -9.43 BE)
Steroids Withametelin (8 NBI and − 8.0 BE), withanolide-A (1-HB, 7-NBI and Asp66, Arg67, Gln85, Val367, Asn370, Phe374, Tyr449, [41,56,57]
− 7.7 BE), echinacin (2-HB, 6-NBI and − 7.9 BE), stigmasterol (2-IR Leu452, Leu455, Phe456, Glu484, Tyr489, Phe490, Leu492,
and − 7.2 BE), withanolide G (4 HB, 2 HP and − 8.4 BE) Gln493, Ser494.
Quinone Emodin (4 IR and − 6.19), rhein (5 IR and − 8.73) Asn332, Thr333, Asn353, Ser388, Val401, Asn448, Ala464, [12]
Val472, Gly474,
Steroidal saponins Asparoside-C (5 HB and − 7.54 BE), asparoside-D (6 HB and − 7.06 Arg403, Glu406, Gln409, Gln414, Thr415, Lys417, Asp420, [16]
BE), shatavarin-I (Asparoside-B) (5 HB and − 6.52 BE), shatavarin-X Lys444, Gly447, Tyr449, Tyr453, Glu484, Ser494, Gly496,
(6 HB and − 6.43 BE), racemoside-A (3 HB and − 6.23) Gly496, Gln498, Gly502
Alkaloid Chelidimerine (2 HB, 3 HP and − 8.2 BE), Withanone (1 HB, 5 HP and Asp66, Arg67, Leu335, Phe338, Gly339, Phe342, Asn343, [57]
− 7.8 BE), Norsanguinarine (3 HB, 3 HP and − 7.0 BE), Sanguinarine (1 Asp364, Val367, Leu368, Leu368, Asn370, Ser371, Phe374,
HB, 4 HP and − 6.8 BE), Adlumidine (3 HB, 4 HP and − 6.8 BE), Trp436
Somniferine (2 HB, 4 HP and − 6.7 BE), Fumariline (1 HB, 3 HP and
− 6.4 BE)
Sesquiterpene Badrakemin acetate (3 HB, 5 HP, and − 8.0 BE), Samarcandin (2 HB, 3 Leu335, Phe338, Gly339, Glu340, Asn343, Asp364, Val367, [57]
HP, and − 7.4 BE) Leu368
Plant lignans Pinoresinol-4-O-b-D- glucopyranoside (4 HB, 3 HP, and − 4.9 BE) Cys336, Phe338, Asn343, Asp364, Val367, Leu368, Ser371 [57]
Anthocyanin Pelargonidin 3-glucoside (4 HB, 3 HP and − 6.2 BE) Cys336, Phe338, Asn343, Asn364, Val367, Leu368, Ser371 [57]
Other compounds Cinnamyl acetate (3-HB and − 5.2 BE), barlerinoside (7-HB, 9-NBI Arg403, Asp405, Glu406, Gln409, Lys417, Tyr449, Tyr453, [47,56]
and − 7.4 BE), deoxytubulosine (1-HB, 8-NBI and − 7.2 BE) Arg454, Leu455, Phe456, Ser469, Glu471, Glu484, Gly485,
Tyr489, Phe490, Leu492, Gln493, Ser494, Gly496, Asn501,
Tyr505
Standards Remidesvir (3 IR and − 5.94 BE), chloroquine (3 IR and − 8.98), Arg403, Glu406, Tyr453, Thr467, Pro468, Cys469, Gly471, [12,16,41]
hydroxychloroquine (4 IR and − 7.82 BE) Val472 [16]
ACE2 (host protein acting as CoV-2 receptor)
Class Small molecule inhibitors Interacting residues with different classes of phytocompounds References
Organo-sulfur Allyl disulfide (3 IR and − 12.84 BE), allyl trisulfide (2 IR and Lys94, Gln98, Gln101, Gln102, Asn103, Gly205, Asp206, [82]
− 12.76 BE), allyl (E)-1-propenyl disulfide (2 IR and − 9.07 BE), Glu208, Val209, Asn210, Ala396, Lys562, Ser563, Pro565,
allyl methyl trisulfide (2 IR and − 12.50 BE), diallyl tetrasulfide (4 Trp566
IR and − 14.06 BE), 1,2-dithiole (2 IR and − 13.21 BE), 1,2-dithiole
(1 IR and − 7.89), allyl (Z)-1-propenyl disulfide (T7) (2 IR and
− 9.04 BE), 2-vinyl-4H-1,3-dithiine (3 IR and − 11.83 BE), 3-vinyl-
1,2-dithiacyclohex-4-ene (3 IR and − 10.57 BE), carvone (2 IR and
− 8.58 BE), trisulfide, 2-propenyl propyl (4 IR and − 14.01 BE),
methyl allyl disulfide (3 IR and − 10.32 BE), diacetonalcohol (2 IR
and − 9.71 BE), trisulfide, (1E)-1-propenyl 2- propenyl (2 IR and
− 9.57 BE), allyl sulfide (3 IR and − 9.38 BE), 1-propenyl methyl
disulfide (2 IR and − 8.06 BE), trisulfide, (1Z)-1-propenyl 2-
propenyl (2 IR and − 8.06 BE).
Tannins Punicalin (5 IR and − 7.353 BE), punicalagin (4 IR and − 7.144 BE), Asp30, Asn33, His34, Glu35, Glu37, Asp38, Tyr41, Ser280, [79]
ellagic acid (4 IR and − 6.85 BE), gallic acid (4 IR and − 5.24 BE), Pro289, Asn290, Ile291, Asp292, Arg393, Lys353, Asp367,
(continued on next page)
6
Table 1 (continued )
pedunculagin (4 HB, 4 HPI and − 7.2 BE), punigluconin (5 HB, 5 HPI Ala386, Ala387, Gln388, Pro389, Arg393, Phe428, Lys441,
and − 6.6 BE), chebulagic acid (1 HB, 6 HPI and − 6.6 BE), Gln442, Thr445.
chebulinic acid (4 HB, 3 HPI and − 6.8 BE), gallotannins (4 HB, 7 HPI
and − 7.1 BE).
Flavonoid Hesperidin (4 IR and − 9.167 BE), chrysin (3 IR and − 7.146 BE), Thr27, Lys31, His34, Glu35, Glu37, Asp38, Gln42, Asn63, [12,100]
rutin (6 IR and − 3.41 BE), vitexin (7 IR and − 5.71 BE), apigenin (5 Thr125, Ile126, Thr129, Asn137, Pro138, Gly139, Lys353
IR and − 3.75 BE), quercetin (5 IR and − 4.11 BE)
Quinone Emodin (3 IR and − 9.83 BE), Rhein (- 7.423 BE) Asp67, Ala71, Lys74 [12]
Terpenoid Thymol and iso-thymol (1 H-donor and − 4.74 BE), m-eugenol (4 IR Lys26, Thr27, Asp30, Lys31, Asn33, His34, Glu35, Asp38,
and − 2.53 BE), p-thymol (3 IR and − 2.75 BE), carvacrol (7 IR and Glu37, Leu39, Phe40, Gln42, Asn90, Thr92, Val93, Gln96, [1,87,100]
− 3.31 BE), costunolide (4 IR and − 4.0 BE), cynaropicrin (5 IR and Tyr127, Ser128, Glu145, Asn 149, Trp271, Arg273, Phe274,
− 3.06 BE), bharangin (4 IR and − 4.36 BE), andrographolide (6 IR His345, Pro346, Thr347, Ala348, Trp349, Asp350, Lys353,
and − 4.53 BE), beta-pinene (5 IR and − 5.22 BE), spathulenol (6 IR Asp367, Lue370, Thr371, His373, His374, Glu375, Asp382,
and − 4.98 BE), vetiverol (6 IR and - 4.96 BE), cucurbitacin B (6 IR Tyr385, Ala387, Gln388, Pro389, Phe390, Arg393, Asn394,
and − 5.36 BE), alpha-bisabolol (7 IR and − 5.69 BE), 6-shogaol (6 IR His401, Glu402, Glu406, Ser409, Gln442, Thr445, Leu503,
and − 3.33 BE), 6-gingerol (6 IR and − 3.49 BE), beta-sitosterol (7 IR Phe504, His505, Asn508, Arg514, Tyr515, Lys562
and − 4.88 BE), linoleic acid (6 IR and − 2.07 BE), glycyrrhizinic
acid (4 HB, 2 Pi-Alkyl, 1CHB, 9 VDW and − 9.5 BE), maslinic acid (4
HB, 3 Pi-Alkyl, 5 VDW and − 8.5 BE), obacunone (1 HB, 1 Pi-sigma, 1
Pi-Pi T shaped, 2 Pi-Alkyl, 8 VSW and − 8.1 BE), epoxyazadiradione
(2 Alkyl/Pi-Alkyl, 1 Pi-Sigma, 7 VDW and − 8.0 BE),
azadiradionolide (3 HB, 3 Alkyl/Pi-Alkyl, 6 VDW and − 8.0 BE),
Ursolic acid (3 HB, 3 Pi-Alkyl, 7 VDW and − 7.4 BE), gedunin (1 HB,
3 Alkyl/Pi-Alkyl, 1 Pi-Sigma, 1 CHB, 7 VDW and − 7.3 BE).
Alkaloids Pellitorine (5 IR and − 3.4 BE), vasicine (5 IR and − 6.21 BE), Asp30, Lys31, Asn33, His34, Glu35, Glu37, Asp38, Phe40, [100]
piperidine (9 IR and − 4.31 BE), piperine (5 IR and − 4.1 BE) Asp350, Lys353, Pro389, Phe390, Arg393, Asn394,
Standards Lopinavir (9 IR and − 7.5 BE), umifenovir (7 IR and − 6.5 BE), His34, Glu37, Thr276, Asn290, Ile291, Met366, Asp367, [10,79]
Hydroxychloroquine (10 IR and − 7.1 BE) Leu370, Gln388, Pro389, Arg393, Lys403, Glu406, Ser409,
Leu410, Ala413, Lys441, Thr445, Ser494, Tyr495, Gly496,
Tyr505
TMPRSS2 (host protease)
Tannins Punicalin (5 IR and − 8.168 BE), punicalagin (6 IR and − 7.358 BE), Arg87, Ala88, Arg91, Asp92, Asn97, Asp129, Tyr401, Met404, [79]
ellagic acid (2 IR and − 6.829 BE), gallic acid (5 IR and − 5.709 BE) Arg405, Gly408
Steroidal lactone Withaferin-A (2 HB, 19 IR and − 5.60 BE), Withanone (1 HB; 18 HP His296, Glu299, Tyr337, Lys342, Glu389, Asp435, Ser436, [49]
and − 4.30 BE) Cys437, Gln438, Asp440, Ser441, Thr459, Ser460, Trp461,
Gly462, Ser463. Gly464, Cys465, Ala466, Gly472, Val473
Caffeate ester Caffeic acid phenethyl ester (2 HB; 17 HP and − 6.20 BE) Cys281, Val280, His296, Cys297, Glu299, Leu302, Asp435, [49]
Ser436, Cys437, Gln438, Gly439, Asp440, Ser441, Thr459,
Ser460, Trp461, Gly462, Gly464, Cys465
Standards Camostat (5 IR and − 7.069 BE), Camostat mesylate (1 HB and 20 Arg87, Asn97, Phe99, Met404, Arg405, Val275, Gln276, [79]
HPI and -5.9 BE) Val278, Val 280, His296, Cys297, Leu302, Asp435, Ser436, [49]
Cys437, Gln438, Gly439, Ser441, Thr459, Trp461, Gly462,
Cys465, Ala466, Gly472, Val473
Furin (host protein)
Class Small molecule inhibitors References
Tannins Punicalin (7 IR and − 9.725 BE), punicalagin (4 IR and − 9.385 BE), His194, Gly255, Pro256, Pro256, Glu257, Asp258, Asp259, [79]
ellagic acid (5 IR and − 7.801 BE Thr262, Arg298, Cys303, Asp306, Gly307, Ser311, Gly366,
Ser368, Thr365, Arg 490, Trp531, Ala532,
Standards Sulcanozole (4 IR and − 6.923 BE) Val263, Phe528, Trp531, Ala532 [79]
Papain-like protease/nsp3 (viral protease)
Terpenoid, Flavonoid Oleonolic acid (4 IR and − 10 BE), ursolic acid (5 IR and − 9.7 BE), 3β- His89, Trp106, Ala107, Asp108, Asn109, Val159, Gly160, [55]
acetoxyolean-12-en-27-ioc acid (3 IR and − 9.5 BE), Isovitexin (5 IR Gu161, Leu162, Pro248, Tyr264
and − 9.3 BE)
3 Chymotrypsin-like protease/nsp5 (viral protease)

Flavonoid Epigallocatechin (6 IR and − 7.0 BE), gallocatechin (6 IR and − 7.1 Lys5, Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, [20,57,66,67,
BE) catechin (6 IR and − 7.1 BE), epicatechin (6 IR and − 7.2 BE), Met49, Tyr53, Tyr54, Pro108, Lys137, Phe140, Leu141, 73,109]
catechin gallate (6 IR and − 7.2 BE), epigallocatechin gallate (9 IR Asn142, Gly143, Ser144, Cys145, His163, His164, Met165,
and − 7.6 BE), epicatechin gallate (10 IR and − 8.2 BE), Glu-166, Leu-167, Pro168, His172, Asp187, Arg188, Gln189,
gallocatechin-3-gallate (9 IR and − 9.0 BE), kaempferol (4 HB, 6 Thr190, Ala191, Gln192, Gly195, Asp197, Thr199, Asn238,
HPI and − 8.58 BE), quercetin (8 IR and − 6.58), luteolin-7- Tyr239, His246, Leu271, Leu272, Leu286, Leu287, Glu288,
glucoside (10 IR and − 8.17 BE), myricetin (4 IR and − 6.15 BE), Asp289.
scutellarin (2 IR and − 7.13 BE), isoflavone (2 IR and − 5.69 BE),
Quercetin-3-O-rutinose (6 HB, 1 PS and − 9.2 BE), Quercetin-7-O-
glucuronide (6 HB, 1 PC, 1 PS, 1 PP, 1 Pal and − 8.4 BE), quercetin-
3′-O-glucuronide (6 HB, 1 PS, 2 Pal and − 8.5 BE), quercetin-3-O-
glucuronide (3 HB, 1 PS, 1 PC, 1 Pal and − 8.5 BE), quercetin-7-O-
sulfate (6 HB, 1 PS, 1 Pal and − 8.4 BE), quercetin-3-O-sulfate (4 HB,
1 PS, 1 Pal and − 7.6 BE), quercetin-3′-O-sulfate (6 HB, 1 PC, 3 PS
7
and − 8.1 BE), quercetin (4 HB; 1 PS, 2 Pal and − 7.5 BE), kaempferol-
3-O-rutinose (nicotiflorin) (4 HB, 1 PS, 1 Psi, 1 PP and − 8.9 BE),
kaempferol-4′-O-glucuronide (4 HB, 3 Pal and − 8.0 BE),
kaempferol-3-O-glucuronide (6 HB, 1 PS, 1 PP, 1 Psi and − 8.3 BE),
kaempferol-7-O- glucuronide (4 HB, 2 PS, 1 Psi, 2 Pal and − 8.3 BE),
kaempferol-7-O-sulfate (3 HB, 1 PS, 1 PP, 2 Pal and − 8.3 BE),
kaempferol-4′-O-sulfate (4 HB, 1 Pal and − 8.2 BE), kaempferol-3-
O-sulfate (3 HB, 1 PS, 1 Pal and − 7.3 BE), kaempferol (1 HB, 2 PS, 2
Pal and − 7.2 BE), 5,7,3′4’ - tetrahydroxy2’-(3,3- dimethylallyl)
isoflavone (14 IR and − 16.35 BE), myricitrin (16 IR and − 15.64 BE),
methyl rosmarinate (16 IR and − 15.44 BE), 3,5,7,3′,4′,5′-
hexahydroxy flavanone – 3 – O – beta – D glucopyranoside (13 IR
and − 14.42 BE), (2S)-eriodictyol 7-O-(6′′ -Ogalloyl)-beta-D-
glucopyranoside, (15 IR and − 14.41 BE), calceolarioside B (16 IR
and − 19.87 BE), myricetin 3-Obeta-D-glucopyranoside (17 IR and
− 13.70 BE); licoleafol (13 IR and − 13.63 BE), amaranthin (16 IR
and − 12.67 BE), peonidin 3-O-glucoside (5 HB, 7 HP and − 9.4 BE),
kaempferol 3-O-β –rutinoside (4 HB, 6 HP and − 9.3 BE), rutin (2
HB, 6 HP and − 9.2 BE), 4 - (3, 4 - Dihydroxyphenyl) – 7 – methoxy -
5 - [(6 – O – b – D – xylopyranosyl – b – D - glucopyranosyl) oxy] -
2H-1-benzopyran – 2 - one (5 HB and 7 HP), quercetin-3-D-
xyloside (7 HB, 5 HP and − 9.1 BE), quercetin 3-O-a-L-
arabinopyranoside (4 HB, 6 IR and − 9.0 BE), kaempferol 3-ruti
noside 40-glucoside (9 HB, 6 HP and − 8.9 BE), quercetin 3-O-(6′′ -
O-malonyl)-b-D-glucoside (3 HB, 8 HP and − 8.8 BE), idaein (2 HB
and 8 HP), callistephin (3 HB and 8 HP); malvin (4 HB, 8 HP and
− 8.7 BE), luteolin 7-rutinoside (2 HB; 9 HP; − 8.6 BE), cyanin (4 HB;
4 HP; − 8.5 BE), kaempferol 7-O-neohesperidoside (5HB, 7 HP and
− 8.4 BE), rhamnetin 3 sophoroside (5 HB, 4 HP and − 8.3 BE),
myricetin 3-O-b-D-galactopyranoside (5 HB, 2 HP and − 8.2 BE), 2′′ -
O-alpha-L-rhamnopyranosyl-isovitexin (3 HB, 10 HP and − 8.2 BE),
hesperidin methylchalcone (5 HB, 4 HP and − 8.0 BE),
procyanidin-B7 (4 HB, 1 HP, 1 EI and − 8.2 BE), kaempferol 3-
alpha-L-arabinofuranoside-7-rhamnoside (3 HB, 1 HP, 1 EI and
− 8.1 BE), proanthocyanidin-A2 (1 HB, 1 HP, 1 EI and − 8.0 BE), 6-
glucopyranosyl procyanidin B1 (5 HB, 1 HP, and − 7.6 BE),
pavetannin-C1 (4 HB, 1 HP, 1 EI and − 7.3 BE), querceitin 3-O-
robinobioside (6 HB, 8 NBI and − 8.8 BE).
Organosulfur Allyl disulfide (6 IR and − 15.32 BE), allyl trisulfide (4 IR and Leu141, Asn142, Gly143, Ser144, Cys145, His163, Met165, [82]
− 15.02 BE), allyl (E)-1-propenyl disulfide (2 IR and − 13.25 BE), Glu166
allyl methyl trisulfide (4 IR and − 14.36 BE), diallyl tetrasulfide (4
IR and − 14.47 BE), 1,2-dithiole (T6-ACE2) (2 IR and -13.21 BE),
allyl (Z)-1-propenyl disulfide (2 IR and − 12.60 BE), 2-vinyl-4H-
1,3-dithiine (4 IR and − 14.04 BE), 3-vinyl-1,2-dithiacyclohex-4-
ene (3 IR and − 13.83 BE), carvone (1 IR and − 12.36 BE), trisulfide,
2-propenyl propyl (5 IR and − 14.36 BE), methyl allyl disulfide (3
IR and − 13.56 BE), diacetonalcohol (2 IR and − 13.26 BE);
trisulfide, (1E)-1-propenyl 2- propenyl (2 IR and ¡12.00 BE);
(1Z)-1-propenyl 2- propenyl (1 IR and − 11.68 BE)
Terpenoids Glycyrrhizic acid (4 HB, 3 CHB, 12 VDW and − 8.7 BE), 6- Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, [21,31,51,56,
oxoisoiguesterin (5 IR and − 9.1 BE), daturaolone (10 NBI and − 7.3 Met49 Leu50, Tyr118, Arg131, Lys137, Phe140, Leu141, 87]
BE), glycyrrhizin (7 HB; 7 NBI and − 8.2 BE), calendulaglycoside B Asn142, Gly143, Ser144, Cys145, His163, His164, Met165,
(16 IR and − 8.2 BE), calenduloside (15 IR and − 7.9), tenuifolin (6 Glu166, Leu167, Pro168, His172, Asp187, Arg188, Gln189,
HB, HP-2 and 8.8 BE), 7-Deacetyl-7-benzoylgedunin L (1 CHB, 2 Thr190, Ala191, Tyr239, Leu275, Leu286, Leu287
HB, 10 VDW, 1 Pi-Pi T shaped, 1 alkyl, 1 Pi-alkyl, − 9.1), glycyrrhizic
acid (4 HB, 3 CHB, 12 VDW, − 8.7), limonin: 3 HB, 1 pi-donor, 1 CHB,
4 VDW, − 8.7), Obacunone (3 HB, 1 pi-donor, 1 pi-alkyl, 5 VDW,
− 7.5), Dihydroartemisinin (2 HB, 2A, 1 PA and − 7.0 BE)
Sesquiterpene Badrakemin acetate (2 HB, 5 HP and − 8.6 BE), Samarcandin (3 HB, His41, Gly143, Cys145, His163, Glu166, Leu167, Pro168, [57]
2 HP and − 8.5 BE) Gln192
Iridoid glycoside Harpagoside (3 HB, 3 HP and − 6.1 BE) His41, Met49, Leu141, Asn142, Met165, Glu166 [57]
Beta-diketone demethoxycurcumin (1 IR and − 7.02 BE), curcumin (2 IR and His41, Asn119, Phe140, Cys145, His163 [73]
− 6.04 BE); bisdemethoxycurcumin (5 IR and − 7.3 BE)
Beta-hydroxy ketone Zingerol (5 IR and − 5.40 BE) and gingerol (5 IR and − 5.38 BE) Met49, His163, Met165, Glu166, Pro168, Asp187, Arg188, [43]
Gln189, Thr190
Furanocoumarin Bergapten (5-methoxypsoralens) (2 IR and − 5.98 BE) Phe140, His163 [73]
Anthocyanins Delphinidin 3-Sambubioside-5-Glucoside (27 IR and − 12.37 BE); Thr24, Thr25, Thr26, Leu27, His41, Cys44, Met49, Leu50, [27,57]
Delphinidin 3,3′-Di-Glucoside-5-(6-P-Coumarylglucoside) (28 IR Pro52, Tyr54, Gly138, Ser139, Phe140, Leu141, Asn142,
and − 11.59 BE), Gly143, Ser144, Cys145, His163, His164, Met165, Glu166,
2-(3,4,5-Trihydroxyphenyl)-3-[6-[(E)-3-(4-hydroxyphenyl) Leu167, Pro168, Thr169, Gly170, His 172, Val186, Asp187,
acryloyl]-beta-D-galactopyranosyloxy]-5,7-dihydroxy-1- Arg188, Gln189, Thr190, Ala191, Gln192
8
benzopyrylium 2-(3,4,5- Trihydroxyphenyl)-3-[6-[(Z)-3-(4-
hydroxyphenyl) acryloyl]-beta-D-galactopyranosyloxy]-5,7-
dihydroxy-1-benzopyrylium (27 IR and − 10.94 BE),
3-O-[b-D-Glucopyranosyl-(1->2)-[4-hydroxycinnamoyl-(->6)]-
b-D-glucopyranoside](E-), 5-O-(6-O-malonyl-b-D-
glucopyranoside) Pelargonidin 3-O-[b-D-Glucopyranosyl-(1->2)-
[4-hydroxycinnamoyl-(->6)]-b-D-glucopyranoside](E-) 5-O-(6-
O-malonyl-b-D-glucopyranoside (25 IR and − 10.30 BE),
3-< [4,5-dihydroxy-6-(hydroxymethyl)-3-[(3,4,5-trihydroxy-6-<
[hydroxy(4-oxocyclohexa-2,5-dien-1-ylidene)methoxy]methyl
> oxan-2- yl)oxy]oxan-2-yl]oxy>-2-(3,4-dihydroxyphenyl)-7-
hydroxy-5-< [3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]
oxy>-1lambda-chromen-1-ylium (25 IR and − 13.59 BE), Cyanidin
3-(60 ‘-p-coumarylsambubioside) (22 and − 9.58 BE),
Pelargonidin 3-glucoside (4 HB, 5 HP and − 8.1 BE), Cyanidin 3,5-
di-O-glucoside (4 HB, 6 HP and − 6.9 BE), Cyanidin 3-O-rutinoside
(7 HB, 4 HP and − 6.9 BE)
Steroidal lactone Withanoside-II (20 IR and − 11.30 BE), withanoside IV (20 IR and Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, [57,84]
11.02 BE), withanoside-V (27 IR and − 8.96 BE), sitoindoside IX (24 Met49, Leu50, Phe140, Leu141, Asn142, Gly143, Ser144,
IR and − 8.37 BE), Withanolide G (4 HB, 4 HP and − 8.6 BE) Cys145, His163, His164, Met165, Glu166, Leu167, Pro168,
Arg188, Gln189, Thr190, Ala191, Gln192
Alkaloid 10-Hydroxyusambarensine ( 10 IR and − 10.1 BE), His41, Met49, Tyr54, Lys137, Phe140, Leu141, Asn142, [31,57]
cryptoquindoline (3 IR and − 9.7 BE); 6-Oxoisoiguesterin (1 HB, 4 Gly143, Ser144, Cys145, Cys148, Met49, His163, Met165,
IR and − 9.1 BE), N-[(5-methylisoxazole - 3-yl) carbonyl] alanyl-l- Glu166, Leu167, Pro168, Asp187, Gln189, Gln192, Thr199,
valyl-n1- ((1r,2z)-4-(benzyloxy) – 4 – oxo -1- [(3r)-2-oxopyrrolidin-3- Tyr239, Tyr273, Leu275 Leu286, Leu287
yl] methyl] but-2-enyl)-l-leucinamide (3 HB, 3 HPI, − 7.4 BE), 22-
hydroxyhopan-3-one (1 HB, 4 IR and − 8.6 BE), Chelidimerine (2 HB,
6 HP and − 10.2 BE), Somniferine (3 HB, 3 HP and − 8.3 BE),
Adlumidine (5 HB, 2 HP and − 8.2 BE), Withanone (4 HB, 3 HP and
− 8.2 BE), Fumariline (3 HB, 5HP and − 7.8 BE), Sanguinarine (5 HB, 3
HP and − 7.7 BE), Norsanguinarine (3 HB, 5 HP and − 7.5 BE)
Tannins Pedunculagin (5 HB, 9 NBI and − 8.9 BE), punigluconin (6 HB, 12 Thr24, Thr25, Thr26, His41, Cys44, Thr45, Ser46, Tyr54, [41,56,66]
Phenylpropanoids NBI and − 8.5 BE), taraxerol (11 NBI and − 7.2 BE), withametelin (8 Cys145, His163, Thr25, Met49, Phe140, Leu141, Asn142, [51]
Aromatic alcohol NBI and − 7.9 BE), tinosporide (2 HB, 12 NBI and − 8.5 BE), Gly143, Ser144, Cys145, His164, Met165, Glu166, His172, [51]
chebulagic acid (6 HB, 3 NBI and − 6.5 BE), chebulinic acid (9 HB, 9 Ala285, Asp187, Arg188, Gln189, Asp197, Thr199, Tyr239,
NBI and − 8.6 BE), gallotannins (5 HB, 10 NBI and − 8.3 BE), Met276, Leu287, Leu286
cinnamtannin-B1 (3 HB, 4 HP and − 8.4 BE), barlerinoside (7 HB, His41, His164, Gln192, Thr190, Pro168, Met165,
10 NBI and − 7.5 BE) Arg188, Arg187, Val186, Thr190, Gln192, Met49, Met165,
Hydroxycinnamic acid (3 HB, 2A, 1 PA, and − 7.5 BE) Pro168
Phenethyl alcohol (6 HB, 2 PA, − 7.3 BE)
Standards N3 inhibitor (native cocrystal ligand) (8 HB, 6 HPI and − 7.9 BE/28 Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, [20,27,31,67,
IR and − 9.47 BE/23 IR and − 8.12 BE), nelfinavir (9 IR and − 12.20 Glua47, Met49, Leu50, Pro52, Tyr54, Val104, Gln110, Ile106, 73,84,109]
BE); prulifloxacin (10 IR and − 11.32 BE) and colistin (18 IR and Asp153, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145,
− 13.73 BE), x77 (4 HB, 2 PS, 1 Pal, 1 Pam, 1 PP and − 8.4 BE), Ser158, His163, His164, Met165, Glu166, Leu167, Pro168,
ribavirin (5 IR and − 5.43 BE), lopinavir (3 HB, 3 HP and − 9.41 BE), Gly170, Hie172, Asp187, Arg188, Gln189, Thr190, Ala191,
ritonavir (2 HB, 3 IR and − 6.8 BE), l Gln192, Val202, Ile249, Pro293, Phe294 Val297.
X77 (4 HB, 2 PS, 1 PA1, 1 Pam, 1 PP and − 8.4 BE)
RNA dependent RNA polymerase/nsp12 (viral replicase)
Flavonoid Theaflavin (8 HB, 2 PA and − 9.1 BE), quercetin-3-O- (rutin) (9 HB, Asp452, Lys545, Arg553, Ala554, Arg555, Thr556, Met615, [20]
1 Psi and − 8.5 BE), quercetin-7-O-glucuronide (6 HB, 1 PA and Trp617, Asp618, Tyr619, Pro620, Lys621, Cys622, Asp623,
− 8.2 BE), quercetin-3′-O-glucuronide (5 HB; 1 PAm; − 8.2 BE), Arg624, Thr687, Asn691, Ser759, Asp760, Asp761, Ser778,
quercetin-3-O-glucuronide (6 HB; 2 PA; 1 Pal; − 8.0 BE), quercetin- Ile779, Glu796, Lys798, Cys799, Trp800, Thr801, Glu811,
7-O-sulfate (6 HB, 1 PC, 1 Pal, and − 8.0 BE), quercetin-3-O-sulfate Cys813, Ser814
(2 HB, 2 PA and − 7.1 BE), quercetin-3′-O-sulfate (6 HB, 1 PC, 1 Pal
and − 8.1 BE), quercetin (3 HB, 2 Psi and − 7.4 BE), kaempferol-3-O-
rutinose (4 HB, 2 PA and − 9.2 BE), kaempferol -4′-O-glucuronide
(6 HB, 1 PC and − 8.3 BE), kaempferol-3-O-glucuronide (6 HB, 2 PA,
2 Pal and − 7.9 BE), kaempferol-7-O-glucuronide (8 HB, 1 PC and
− 7.9 BE), kaempferol-7-O-sulfate (4 HB, 1 PC, 2 PA, 2 Pal and − 7.3
BE), kaempferol-4′-O-sulfate (1 HB, 2 PA and − 6.7 BE),
kaempferol-3-O-sulfate (1 HB, 2 PA and − 6.7 BE), kaempferol (2
HB, 2 Psi and − 7.2 BE)
Terpenoids Glycyrrhizic acid (7 HB, 1 CHB, 1 pi-alkyl, 16 VDW and − 9.9 BE), His439, Asp452, Tyr456, Met542, Lys545, Ala547, Ile548, Ser [87]
limonin (2 HB, 2 pi-alkyl, 1 pi-pi T shaped, 10 VDW and − 8.2 BE), 7- 549, Ala550, Lys551, Arg553, Ala554, Arg555, Thr556,
Deacetyl-7-benzoylgedunin (1 HB, 1 Alkyl/pi-alkyl, 2 CHB, 1 pi- Val557, Ala558, Gly616, Trp617, Asp618, Tyr619, Pro620,
anion, 3 pi-cation, 6 VDW and − 8.2 BE), limonin glucoside (3 HB, 1 Cys622, Asp623, Arg624, Ser682, Asp760, Asp761, Ala762,
CHB, 4 Alkyl/Pi-Alkyl, 9 VDW and − 8.2 BE), 7- -deacetylgedunin (1 Val763, Ala797, Lys798, Trp800, His810, Glu 811, Phe812,
HB, 2 CHB, 1 Pi-Alkyl, 1 Pi-sigma, 1 Pi-anion, 5 VDW and − 8.1 BE), Ser814, Arg836
obacunone (2 HB, 1 Alkyl, 1 Pi-Anion, 8 VDW and − 7.8 BE)
Standards Remdesivir (3 IR and − 6.3 BE), favipiravir (3 IR and − 3.6 BE) Lys551, Arg553, Arg555, Asp623, Ser682 [41]
Helicase/nsp13 (viral protein)
Flavonoids [46]
9
Tomentodiplacone B (9 IR and − 8.4 BE), osajin (4 IR and − 8.2 BE), Val6, Asn9, Arg21, Arg22, Pro23, Phe24, Glu128, Arg129,
sesquiterpene glycoside (9 IR and − 8.2 BE), rhamnetin (9 IR and Leu132, Phe133, Glu136, Arg178, Asn179, Pro234, Pro238,
− 8.1 BE), silydianin (6 IR and − 8.1 BE) Ser310, Pro406, Ala407, Pro408, Asp534, Arg560
Standards Nelfinavir (6 IR and − 6.2 BE), remdesivir (8 IR and − 6.8 BE), Val6, Arg21, Arg129, Leu132, Glu136, Lys139, Glu142, [46]
prulifloxacin (7 IR and − 8.1 BE) Asn177, Asn179, Tyr180, Pro234, Pro238, Cys309, Met378,
Asp383, Pro406, Ala407, Pro408, Arg409, Thr410, Leu412,
Leu417, Arg560
Endoribonuclease/nsp15 (viral protein)
Flavonoid Naringin (5 IR and − 7.8 BE), taxifolin (6 IR and − 7.2 BE), luteolin His235, ASP240, Gln245, Gly248, His250, Lys290, Val292, [106]
(5 IR and − 7.2 BE), apigenin (4 IR and − 7.2 BE), myricetin (4 IR and Ser294, Val339, Glu 340, Thr341, Tyr343, Pro344, Leu346
− 7.0 BE), wogonin (3 IR and − 6.9 BE), epigallocatechin (3 IR and
− 6.8 BE), chlorogenic acid (6 IR and − 6.8 BE), afromosin (4 IR and
− 6.7 BE), rutin (5 IR and − 7.8 BE), silymarin (IR and − 8.0 BE).
Beta-diketone Demethoxycurcumin (5 IR and − 7.51 BE), quercetin (4 IR and His235, Glu340, Thr341, His250, Lys290; Ser294, Gly248 [73]
− 6.49 BE), bisdemethoxycurcumin (1 IR and − 6.56 BE), curcumin
(1 IR and − 6.48 BE), myricetin (4 IR and − 6.52 BE), bergapten (4 IR
and − 5.92 BE), scutellarin (4 IR and − 6.97 BE), isoflavone (2 IR and
− 5.47 BE)
Terpenoid Saikosaponin-V (8 HB, 9 HP and − 8.35 BE), saikosaponin-U (8 HB, Gly230, Ala232, Glu234, Hip235, Asp240, Gly245, Leu246, [75,106]
8 HP and − 7.27 BE), saikosaponin-C (6 HB, 9 HP and − 6.98 BE), Gly247, Gly248, His250, Asn278, Lys290, Cys291, Val292,
saikosaponin-K (5 HB, 10 HP and − 6.79 BE), saikosaponin-1b (4 Cys293, Met331, Ala232, Trp333, Val339, Glu340, Thr341,
HB, 8 HP and − 6.36 BE), alpha-amyrin (1 IR and − 8.1 BE), pomolic Tyr343, Pro344, Leu346
acid (2 IR and − 7.9 BE), carnosol (2 IR and − 7.8 BE), arjunolic acid
(1 IR and − 7.6), asiatic acid (5 IR and − 7.4 BE), betulinic acid (1 IR
and − 7.3 BE), platanic acid (5 IR and − 7.3 BE), alphitolic acid (1 IR
and − 7.2), Asiatic acid (5 IR and − 7.4), ursonic acid (5 IR and − 8.4
BE).
Coumarin Beta sitosterol (1 IR and − 8.1 BE), gliotoxin (3 IR and − 6.7 BE), His235, Gly248, His250, Lys290, Val292, Cys293, Ser294, [106]
psoralen (5 IR and − 6.7 BE), carinatine (4 IR and − 6.6 BE), Thr341, Tyr343.
rhinacanthin (6 IR and − 6.5 BE), caffeic acid (4 IR and − 6.3 BE),
coriandrin (3 IR and − 6.2 BE), scopoletin (5 IR and − 6.1 BE),
cordycepin (4 IR and − 5.6 BE), ricinoleic acid (3 IR and − 5.0 BE),
alpha asarone (1 IR and − 4.9 BE), valproic acid (4 IR and − 4.6 BE)
Organosulfur allicin (3 IR and − 3.8 BE) His235, Thr341, His250 [106]
Alkaloid Taspine (4 IR and − 7.3 BE), ajmalicine (5 IR and − 8.1 BE), His235, Thr341, Gly248, His250, Lys290, Glu340 [106]
reserpine (4 IR and − 7.4)
Steroids Asparoside-C (5 HB and − 7.16 BE), asparoside-F (7 HB and − 6.6 Gly230, Ala232, Glu234, Hip235, Val339, Asp240, His243, [16]
BE), asparoside-D (6 HB and − 6.4 BE), rutin (5 HB), racemoside-A Gln245, His250, Asn278, Val292, Glu340, Thr341, Leu346
(4 HB and − 5.99)
Standards Hydroxychloroquine (4 IR and − 5.8 BE), Nelfinavir (4 IR and − 7.3 Thr26, His235, His250, Gly248, Lys290, Val-292, Ser294,
BE), ribavirin (9 IR and − 5.84) Thr341, Tyr 343, Pro344, [73,106]
2′-O- methyl transferase/nsp16 (viral protein)
Flavonoids, Alkaloids, Eryvarin-M (9 IR and − 8.6 BE), silydianin (9 IR and − 8.5), osajin (6 Asp6873, Asn6899, Asp6897, Amet6929, Leu6898, Asn6841, [46]
others IR and − 8.2 BE), raddeanine (8 IR and − 8.2 BE) Lys6844, Cys6913, Lys6968, Phe6947, Lys6944, Asn6899,
Asp6928, Cys6913, Gly6911, Leu6898, Met6929, Asp6897,
Asp6928, Met6929, Cys6913, Leu6898, Gly6869, Cys6898,
Asp6928, Asp6897, Asp6912, Cys6913, Leu6898, Asp6897,
Gly6871, Asn6811, Met6929, Phe6947.
Standards Nelfinavir (9 IR and − 8.2 BE), remdesivir (9 IR and − 7.0 BE), Leu6898, Tyr6930, Gly6871, Pro6932, Lys6968, Lys6844, [46]
prulifloxacin (12 IR and − 7.6 BE) Gly6911, Met6929, GLy6969, Pro6932, Lys6968, Lys6844,
Leu6898, Lys6996, Glu7001, Lys6844, Lys6844, Lys6968,
Asp6928, Met6929, Cys6913, Asp6897, Asn6841, Gly6871,
Leu6898, Phe6947, Tyr6930, Asp6897, Asn6899, Pro6932,
Asp6931
Note: BE - binding energy, HB - hydrogen bond, HP/HPI - hydrophobic interactions, NBI = non-bonding interactions, IR-interacting residues, EI- electrostatic in
teractions, CHB –carbon-hydrogen bond, VDW – van der Waals interactions. PS: π-sulfur; Pal: π-alkyl; PP: π-π; PA: π-anion; PC: π-cation; Psi: π-sigma; Pam: π-amide; Pi-
H = π-hydrogen bond, PA- π-alkyl; A-alkyl.
5.1. Papain-like protease (PLpro)/nsp3 represents a promising drug target [52]. The docking score and the
prediction of the molecular interactions showed that phytochemicals
Papain-like protease (PLpro)/nsp3 is a multidomain transmembrane oleanolic acid, 3β-acetoxyolean-12-en-27-oic, and isovitexin could effi
protein with an active site containing catalytic triad residues (Cys-111, ciently interact with the PLpro mainly by hydrogen bond [55]. Another
His-272 and Asp-286) in between thumb and palm protein domains study showed that catechins from green tea can interact to the S1
(Figure-8). This protein is autocleaved from nsp3 protein via its intrinsic ubiquitin-binding site of PLpro which might lead to inhibition of its
proteolytic activity. PLpro can also perform deISGylation of host pro protease enzymatic function as well as abrogation of SARS-CoV-2
teins which could lead to inhibition of host innate immune response [18, inhibitory role on interferon-stimulated gene system [18](Table 1).
40]. Due to its key role in viral replication and disease pathogenesis, it
10
Fig. 9. The interaction sites of several classes of phytocompounds on different domains of SARS-CoV-2 3-chymotrypsin like protease (3CLpro) including
the catalytic dyad residues (His-41 and Cys-145; shown in purple). (For interpretation of the references to colour in this figure legend, the reader is referred to the
Web version of this article.) (3CLpro domain organization is adapted from Joshi et al., 2020 [40])
Fig. 10. Molecular structure of SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and the interaction sites of flavonoids and and terpenoids on its different
domains(protein domain organization is adapted from Zhang et al., 2020[120])
5.2. 3-chymotrypsin-like protease (3-CL pro)/nsp5 phytocompounds bind firmly at the catalytic dyad (Cys-145 and His-41)
and other crucial amino acid residues (Phe-140, Leu-141, Asn-142,
The 3CLpro, also called as viral main protease (or nsp5), consists of Gly-143, Ser-144, Glu-166, His-163, His-164, Met-165, Leu-167,
N-terminal finger domain (1–9 amino acids), domain-1 (10–99 amino Pro-168, His-172, Asp-187, Arg-188) of 3-CL pro via making hydrogen
acids), domain-2 (100–182 amino acids) and the C-terminal domain-3 bonds, hydrophobic bonds and other interactions (like Pi-alkyl and Pi-Pi
(amino acid residues 198–303) [40,94]. The catalytic dyad consists of T-shaped, van der Waals etc). Phytocompounds extracted from Avin
His-41 and Cys-145 (Fig. 9). The dimerization of 3-CLpro is required for cennia officinalis and Iranian medicinal plants have also been proposed
its proteolytic activity. as inhibitors of 3-CLpro [51,57]. Tanshinones, a class of natural phy
In-silico screening followed by molecular docking analyses suggested tocompounds have been found to inhibit 3-CLpro activity of SARS-CoV
that the phytochemicals bisdemethoxycurcumin, scutellarin, desme in-vitro enzymatic assay studies (Park et al., 2012[115]). Likewise, as
thoxycurcumin, quercetin, myricetin, luteolin and mundulinol could listed in Table-1 and shown in Figure-9, several phytocompounds have
potentially inhibit 3-CL pro as these compounds exhibit low binding ability to block 3-CLpro preferentially by interacting with its domain-1
energy [25,73]. Another study recommended certain compounds such and domain-2.
as catechin, naringenin, kaempferol, glucosides, quercetin, and
epicatechin-gallate as potential inhibitors of 3CLpro [43]. The phyto 5.3. RNA dependent RNA polymerase/nsp12
compounds like melitric acid-A, salvianolic acid-A, withanoside-V, and a
few bioactive compounds from Calendula officinalis showed higher With the help of accessory subunits nsp7 and nsp8, the catalytic
binding affinities with 3-CLpro than the N3 and lopinavir (standards). subunit nsp12 of RdRp plays a crucial role in the transcription cycle of
Also, they could have important interactions with the amino acid resi SARS-CoV-2 [88]. Its structure is highly similar to SARS-CoV. The
dues of the catalytic dyad [20,21,24,56,84]. In another study, a database nucleotide triphosphate (NTP) entry channel comprises positively
of medicinal plants consisting of more than 30,000 potential anti-viral charged amino acid residues Lys-545, Arg-553, and Arg-555. The right
phytochemicals was screened, and the top hits that could inhibit hand-like structure of the RdRp domain is further divided into a
SARS-CoV-2 3CLpro function and viral RNA replication were selected. finger-domain (398–581 and 628–687 amino acids), a palm-domain
These hits include myricitrin, 5,7,3′ ,4′ -tetrahydroxy2’-(3,3- dimethy (582–627 amino acids and 688–815 amino acids), and a thumb
lallyl) isoflavone, methyl rosmarinate, (2S)-eriodictyol domain (816–919 amino acids). Two Zn ions are also required to sta
7-O-(6′′ -O-galloyl)-beta-D-glucopyranoside, calceolarioside B, 3,5,7,3′ , bilize three-dimensional structure of the RdRp [3,45] (Figure-10).
4′ ,5′ -hexahydroxy flavanone-3-O-beta-D-glucopyranoside, myricetin Tyr-618, Asn-691, Met-755, Ile-756, Leu-757, Ser-759, Asp-760,
3-O-beta-D-glucopyranoside, licoleafol, amaranthine, colistin, nelfina Asp-761, Val-763, Phe-812, Cys-813 and Ser-814 are some of the
vir, and prulifloxacin [67]. Terpenoids (6-Oxoisoiguesterin and amino acids residues that are crucial in interacting with the nsp7/8
22-hydroxyhopan-3-one) and some anthocyanin derivatives could sta complex. In addition, Asp-761 and Asp-762 are active site residues [3].
bly interact with catalytic dyad and other crucial residues via hydrogen Several compounds have been analyzed in-silico against these
and hydrophobic interactions [27,31].Epigallocatechin, gallocatechin, important sites to investigate their possible antiviral viral targets for the
and epicatechin from green tea also showed the potential to restrict the SARS-CoV-2. Green tea polyphenols EGCG and theaflavin gallates
activity of 3-CL pro (Ghosh et al., 2020[101]). Similarly, several including theaflavin-3-O-gallate (TF2a), theaflavin-3′ -digallate (TF2b)
11
Table 2
Effect of phytocompounds on targeted SARS-CoV-2 proteins/replication/infection in cell-free and cell-based studies.
Sl Crude extract/compound Virus/RNA/enzyme Inhibitory assay Dosage (IC50/EC50/CC50) References
no inhibition/cytotoxicity
Flavonoid
01 Baicalein 3CLpro - Invitro IC50 0.39 ± 0.11 μM [50]

SARS-CoV-2 replication Vero cells EC50 2.92 ± 0.06 μM [50]
Cytotoxicity Vero cells CC50 >500 μM [50]
02 Baicalin 3CLpro In-vitro IC50 83.4 ± 0.9 μM [50]
03 Scutellarein 3CLpro In-vitro IC50 5.80 ± 0.22 μM [50]
04 Dihydromyricetin 3CLpro In-vitro IC50 1.20 ± 0.09 μM [50]
05 Quercetagetin 3CLpro In-vitro IC50 1.24 ± 0.14 μM [50]
06 Myricetin 3CLpro In-vitro IC50 2.86 ± 0.23 μM [50]
07 Baicalin 3CLpro (FRET) In-vitro IC50 6.41 ± 0.95 μM [78]
Replication inhibition Vero E6 EC50 27.87 ± 12.95 μM [78]
Cytotoxicity Vero E6 CC50 >200 μM [78]
08 Baicalein 3CLpro (FRET) In-vitro IC50 0.94 ± 0.20 μM [78]
Replication Vero E6 EC50 2.94 ± 1.19 μM [78]
Cytotoxicity Vero E6 CC50 >200 μM [78]
09 Theaflavin 3CLpro (FRET) In-vitro IC50 8.44 μg/mL [39]
Cytotoxicity HEK293T CC50 >40 μg/mL [39]
10 Myricetin 3CLpro (FRET) In-vitro IC50 0.2 μM [107]
11 Baicalin 3CLpro (FRET) In-vitro IC50 34.71 μM [103]
12 Herbacetin 3CLpro (FRET) In-vitro IC50 53.90 μM [103]
13 Pectolinarin 3CLpro (FRET) In-vitro IC50 51.64 μM [103]
Terpenoids
14 Glycycrrhizin (triterpenoid 3CLpro In-vitro IC50 30 μM (0.024 mg/mL) [86]
saponin) Virus titer tit Vero cells TCID50 0.44 mg/mL [86]
Cytotoxicity Vero cells 4 mg/mL (no cytotoxicity) [86]
15 Δ9-Tetrahydro cannabinol Antiviral activity Vero cells EC50 13.17 μM [97]
Cytotoxicity Vero cells CC50 29.34 μM [97]
9
16 Δ -THC Antiviral activity Vero cells EC50 10.25 μM [97]
17 CBN Antiviral activity Vero cells EC50 11.07 μM [97]
18 CBD Antiviral activity Vero cells EC50 7.91 μM [97]
19 CBDA Antiviral activity Vero cells EC50 37.61 μM [97]
20 Andrographolide SARS-CoV2 infection in- Vero E6 EC50 6.58 μM [42]
vitro
Plaque reduction Vero E6 EC50 0.28 μM
Cytotoxicity CC50 27.77 μM
21 Andrographolide Plaque reduction Calu-3 cells EC50 0.034 (μM) [72]
Cytotoxicity a) HepG2 CC50 a) 81.52 μM
b) imHC CC5 b) 44.55 μM
c) HK-2 CC5 c) 34.11 μM
d) Caco-2 CC5 d) 52.30 μM
e) Calu-3 CC5 e) 58.03 μM
f) SH-SY5Y CC5 f) 13.19 μM
22 Arteether (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 31.86 ± 4.72 μM [14]
lactone) Cytotoxicity Vero E6 CC50 >200 μM [14]
23 Artemether (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 73.80 ± 26.91 μM [14]
24 Artemisic acid (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 >100 μM [14]
25 Artemisinin (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 64.45 ± 2.58 μM [14]
26 Artemisone (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 49.64 ± 1.85 μM [14]
27 Dihydroartemisinin SARS-CoV-2 infection Vero E6 EC50 13.31 ± 1.24 μM [14]
(sesquiterpene lactone) Cytotoxicity Vero E6 CC50 31.44 ± 0.73 μM [14]
28 Artesunate (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 12.98 ± 5.30 μM [14]
lactone) Cytotoxicity Vero E6 CC50 55.08 ± 2.32 μM [14]
29 Arteannuin (sesquiterpene SARS-CoV-2 infection Vero E6 EC50 10.28 ± 1.12 μM [14]
lactone) Cytotoxicity Vero E6 CC50 71.13 ± 2.50 μM [14]
30 Cannabidinol SARS-CoV-2 infection Vero E6 CC50 71.13 ± 2.50 μM [14]
Cytotoxicity A549-ACE2 EC50 1.25 μM (SARS CoV2γ) [61]
0.85 μM (SARS CoV2α)
0.86 μM (SARS CoV2β)
0.63 μM (SARS CoV2)
Tannins
31 Punicalin RBD-ACE2 binding assay Invitro IC50 0.14 mg/mL [80]
(ELISA)
32 Corilagin SARS-CoV-2 inhibition Vero EC50 0.13 μmol/L [108]
33 Corilagin RBD-ACE2 binding assay In-vitro IC50 24.9 μM [93]
34 Corilagin (RAI-S-37) (ELISA) HEK293 cell CC50 >100 [93]
35 Corilagin (RAI-S-37) + Cytotoxicity LO2 cells CC50 >100
12
Sl Crude extract/compound Virus/RNA/enzyme Inhibitory assay Dosage (IC50/EC50/CC50) References
no inhibition/cytotoxicity
Flavonoid
36 Remidesivir Cytotoxicity Beas-2B cell CC50 >100 [108]

37 Corilagin (RAI-S-37) Cytotoxicity HEK293 cell transfected EC50 3.33 ± 0.52 μmol/L [108]
38 Corilagin (RAI-S-37) SARS-CoV-2 RdRp inhibition with nsp7 + nsp8 + nsp12 EC50 1.25 ± 0.52 μmol/L [108]
Corilagin (RAI-S-37) SARS-CoV-2 RdRp inhibition HEK293 transfected with EC50 3.65 ± 0.56 μmol/L [108]
SARS-CoV-2 RdRp inhibition nsp7 + nsp8 + nsp12 EC50 1.84 ± 0.27 μmol/L
SARS-CoV-2 RdRp inhibition HEK293 transfected with EC50 0.13 μmol/L
SARS-CoV-2 infection nsp7 + nsp8+nsp12/
nsp10+nsp14
HEK293 transfected with
nsp7 + nsp8+nsp12/
nsp10+nsp14
Vero cells
39 EGCG 3CLpro (FRET) In-vitro IC50 7.58 μg/mL [39]
Cytotoxicity HEK293T CC50 >40 μg/mL
Others
40 Cepharanthine (alkaloid) SARS-CoV2 infection Vero cells EC50 2.8 μM [38]
CC50 12.9 μM
41 Emetine (alkaloid) SARS-CoV2 infection Vero cells EC50 0.000397 μM [38]
CC50 1.53 e + 6 μM
42 6-Gingerol (beta-hydroxy SARS-CoV2 infection Vero E6 EC50 >100 μM [42]
ketone) Cytotxicity Vero E6 CC50 >100 μM
43 Panduratin A SARS-CoV2 post infection Vero E6 EC50 0.81 μM [42]
(Diarylheptanoid) Vero E6 CC50 14.71 μM
SARS-CoV2 pre-entry Vero E6 EC50 5.30 μM
Vero E6 CC50 43.47 μM
Plaque reduction Vero E6 EC50 0.078 μM
SARS-CoV2 infection Calu3 EC50 2.04 μM
Cytotoxicity Calu3 CC50 43.92 μM
Plaque reduction Calu3 EC50 0.53 μM
44 Emetine hydrochloride SARS-CoV-2 virus reduction Vero E6 EC50 0.46 μM [111]
(alkaloid) CPE inhibition Vero E6 EC50 1.5625 μM [111]
Cytotoxicity Vero E6 CC50 56.46 μM [111]
45 Phillyrin (KD-1) Anti-HCoV-229E Vero E6 EC50 64.53 μg/ml [113]
Lignan) Cytopathic effect Vero E6 EC50 63.90 μg/ml [113]
Cytotoxicity Vero E6 CC50 1959 μg/ml [113]
Huh7 CC50 1034 μg/ml [113]
Reduce the production of Vero E6 –CPE (250, 125, and 62.5 μg/ml of KD1) [113]
proinflammatory cytokines (cytopathic TNF-α, IL-6, IL-1β, MCP-1, and IP-10)
effect) at the mRNA levels.
46 Cepharanthine SARS-CoV-2 RNA VeroE6/TMPRSS2 EC50 0.35 μM, [114]
(bisbenzylisoquinoline Cytotoxicity VeroE6/TMPRSS2 CC50 25.1 μM [114]
47 alkaloid) SARS-CoV-2 infection Vero cells EC50 0.878 μM [112]
Lycorine (alkaloid)
48 Digoxin (cardiotonic SARS-CoV-2 infection Vero cells EC50 0.043 μM [110]
glycoside) Cytotoxicity Vero cells CC50 >10 μM [110]
49 Ouabain (Cardiac glycoside SARS-CoV-2 infection Vero cells EC50 0.024 μM [110]
similar to digitoxin) Cytotoxicity Vero cells CC50 >10 μM [110]
50 Herbacetin 3CLpro (FRET) IC50 33.17 μM [71]
51 Pectolinarin 3Clpro (FRET) in-vitro IC50 27.45 μM
52 Rhoifolin 3CLLpro (FRET) in-vitro in-vitro IC50 37.78 μM
Crude extracts
53 Andrographis paniculata extract SARS-CoV2 infection Vero E6 EC50 68.06 μg/ml [42]
Cytotoxicity CC50 >100 μg/ml
54 Andrographis paniculata extract Plaque assay Calu-3 cells EC50 0.036 (μg/mL) [72]
55 Zingiber officinale rhizome Inhibition of SARS-CoV2 Vero E6 EC50 29.19 μg/ml [42]
extract infection
Cytotoxicity Vero cells CC50 52.75 μg/ml
Plaque reduction Vero cells EC50 1.45 μg/ml
56 Boesenbergia rotunda (extract) SARS-CoV2 infection Vero cells EC50 3.62 μg/mL [42]
Vero cells CC50 28.06 μg/mL
57 Scutellaria baicalensis extract 3CLpro assay In-vitro IC50 8.52 ± 0.54 μg/mL [50]
58 Pomegranate peel extract SARS CoV2 RNA replication Vero cells EC50 0.74 ± 0.36 μg/mL [50]
Cytotoxicity Vero cells CC50 >500 μg/mL
RBD-ACE2 binding assay In-vitro IC50 0.06 mg/mL [80]
(ELISA)
13
and theaflavin 3,3′ -digallate (TF3) have the ability to form stable bound region, and a C-terminal domain (CTD). It plays an essential role in viral
conformations with the RdRp protein and could interact with the cata genome packaging and efficient replication. The N protein is highly
lytic site indicating their potential to serve as inhibitors [81]. immunogenic and is produced in high amounts during infection [22,96].
Several alkaloids from Argemone mexicana and Clerodendrum spp. An in-silico screening study revealed emodin, anthrarufin, alizarine,
could be a potential inhibitory candidates against the SARS-CoV-2 RdRp aloe-emodin, and dantron as phytocompounds with good binding af
protein [41,62] (Table-1). finity with the N-terminal domain of N protein. ADMET prediction
revealed that anthrarufin, emodin, aloe-emodin, alizarine, and dantron
5.4. RNA helicase (nsp13) could be potential candidate drugs to treat COVID-19 [69].
It is a multi-functional magnesium ion-dependent protein that be 7. In vitro and in vivo anti-SARS-CoV-2 activities of plant-derived
longs to the helicase superfamily-1 (SF-1) and has 5′ to 3’ based RNA and compounds
DNA unwinding activities [121]. Compounds such as
tomentodiplacone-B, sesquiterpene glycoside, rhamnetin, osajin, and Plant-based polyphenols (such as phenolic acids, anthocyanins,
silydianin have been shown to exhibit better docking results than those lignans, flavonoids, and stilbenes) and carotenoids (such as xantho
of remdesivir, nelfinavir, and prulifloxacin (standards) [46] (Table-1). phylls and carotenes) are being used to generate antivirals against
various coronaviruses. Recent data on plant-derived compounds showed
5.5. Endoribonuclease/nsp15 their potent and significant SARS-CoV-2 inhibition activity in-vitro and
in-vivo. A comprehensive study, conducted by Jia-Tsrong Jan et al.,
Endoribonuclease/nsp15 cleaves RNA genome into multiple sub screened 190 supplements as well as traditional medicines from Chinese
genomic RNAs (sgRNAs). Based on the docking score, phytocompounds herbs to identify the SARS-CoV-2 infection inhibitors in-vitro in Vero-E6
asparoside-C, asparoside-D, asparoside-F, racemoside-A, and rutin (from cells. in-vitro enzymatic assays were coupled with in-silico modelling to
Asparagus racemosus) were found to be effective against nsp15 endor confirm the antiviral activity against SARS-CoV-2 protease and RNA-
ibonuclease [16]. The 100 nano-second based molecular dynamic dependent-RNA-polymerase (Jan et al., 2021). Further, the efficacy of
simulation study and molecular mechanics-generalized born solvent these promising compounds was tested in a hamster challenge model.
accessibility calculations demonstrated that some phytoconstituents This study identified the anti-SARS-CoV-2 activity in nelfinavir, Perilla
such as withanolide-N, ashwagandanolide, withanoside-X, and frutescens, mefloquine, and Mentha haplocalyx [38]. This observation is
dihydrowithaferin-A from Withania somnifera could potentially suppress very encouraging and warrants an urgent need for testing several other
the nsp15 endoribonuclease activity of SARS-CoV-2 [17]. Another study potent phytocompounds in small animal models to speed up the process
revealed the binding capacity of silymarin, sarsasapogenin, ursonic acid, of developing COVID-19 therapeutics.
rosmarinic acid, curcumin, ajmalicine, novobiocin, aranotin, gingerol, A wide range of natural compounds has been proposed to be used in
and alpha terpinyl acetate to nsp15 protein [106]. treating COVID-19(either alone or in combination with FDA-approved
drugs) including ginkgolic acid, shiraiachrome A, resveratrol, and bai
5.6. 2′ -O-methyltransferase (2′ -O-MTase)/nsp16 calein. Moreover, ginkgolic acid is a specific covalent inhibitor of SARS-
CoV-2 cysteine proteases, targeting PLpro and 3-CLpro in-vitro [93]; and
This is a highly conserved protein of coronaviruses. It is known to [15] (please refer Table 2 and 3 for antiviral and immunomodulatory
play an essential role in viral replication and evasion of host cell innate functions of small molecule inhibitors).
immunity [64]. Phytocompounds like eryvarin-M, osajin, raddeanine, In another study, 122 Thai natural products for anti-SARS-CoV-2
and silydianin have been found to exhibit the best docking results [46] activity were screened using fluorescence-based nucleoprotein detec
(Table-1). tion combined with viral plaque reduction assay. This work showed that
the extract of Boesenbergia rotunda and its phytochemical compound,
6. SARS-CoV-2 assembly inhibitors panduratin A reduce SARS-CoV-2 infectivity in Vero E6 cells at pre-entry
and post-infection phases [42]. Artemisinin B, an antimalarial drug
Structural proteins, membrane, envelope and nucleocapsid, play derived from Chinese herbs, also showed anti-SARS-CoV-2 in these cells
essential roles in the assembly and formation of the infectious virion by blocking SARS-CoV-2 at the post-entry level [14].
particles. Therefore, targeting these proteins could be a promising Anti-SARS-CoV-2 activity evaluation of Andrographis paniculata
approach to inhibit virus multiplication and transmission. extract and Andrographolide in human lung epithelial-carcinoma cell-
line (Calu-3) using a high-content imaging platform in combination with
plaque reduction assay showed potent inhibition of SARS-CoV-2 infec
6.1. Envelope protein
tion with minimal cytotoxicity [72]).
In another study, Glycyrrhizin showed potential antiviral activity
E protein (8–12 kDa) is involved in host cell binding, penetration,
against SARS-CoV-2 by inhibiting the viral 3-CL pro that is essential for
virion assembly, and budding. It is a transmembrane ion channel protein
viral replication [86]. Similarly, several other plant-derived compounds
with an N-terminal ectodomain and an endodomain at C-terminus.
including tea polyphenols EGCG, theaflavin, baicalein, and shuan
Structural insights revealed that compounds from Withania somnifera
ghuanglian inhibit 3-CLpro activity and the viral replication in Vero E6
could block the ion channel activity of E protein by binding to the pore
cell line [39,50,78]. Overall, the potent antiviral and anti-inflammatory
region [5].
activities of plant-derived compounds further warrants need of devel
oping phytochemical-based SARS-CoV-2 treatment options.
6.2. Nucleocapsid protein
N protein is a 419 amino acid protein with conserved N-terminal

domain (NTD), Serine/Arginine rich motif (SR) domain, central linker
14
Table 3
Effect of small molecule inhibitors on host factors as well as on different cytokines (immunomodulatory functions)
Sl Compound/ Properties Biological/immune-action Studies in In-vivo models References
no plant
01 Quercetin Impacts on ACE2 and a) Gene silencing Quercetin affected ACE2 expression. In [29]
Furin b) Expression studies addition, it was found that it could alter the
c) Transgenic mouse models expression of 98 of 332 (30%) genes which
encode human proteins that serve as target for
the SARS-CoV-2
02 citral and anti-inflammatory action Inhibits IL-6, IL-10, TNF-α, IL-4, IFNϒ and IL-1β, In macrophages challenges with LPS-induced [98,104]
lemon grass either release or production and NLRP3 mouse ASLN model
inflammasome activation via blocking activites of
proteins, NF-kB,p65, ATP-induced caspase-1
03 Ginsenoside anti-inflammatory action Down-regulates IL-6, TNF-α, mRNA expression II/R induced lung injury in-vivo [102]
via blocking the activation of NF-kB
04 Withaferin-A Immunosuppressant Affect the release of TNF-α, IL-1α, IL-1β, IL-5, IL-3, ATP-stimulated monocyte-derived THP-1 cells. [77,99]
IL-6, IL-8, IP-10, CCL2, MCP-1, SDF-1α, MIP-1α, Also mouse and human islet cells – in vitro.
MIP-1β and GM-CSF.
05 Kaempferol anti-inflammatory action TNF-α, IL-1β, IL-6, IL-8 via inhibiting the human mast cells [105]
activation of PKC θ
06 EGCG Regulation of cytokine Downregulating the IL-6 and IL-6 driven JAK- Primary human melanocytes, human T cells or [18,60]
driven signaling STAT pathway purified CD8+ T cells from PBMC
pathways Similarly by affecting IL-1 driven MAPK pathway
Reduced the protein levels of the receptors
including CD11a, CXCR3, and CCR2 in human T-
lymphocyte cells
– Prevents the cytokine storm and mucous [81]

hypersecretion in COVID-19
07 Cannabidol anti-inflammatory and These effects are mediated by inhibition of pro- COVID 19 Patients https://clinicaltr
immunosuppressive inflammatory cytokine release (e.g. tumor ials.gov/ct2/sh
necrosis factor-a, Interferon-gamma, IL-1b, IL-6, ow/NCT04731116
and IL-17) and stimulation of several anti-
inflammatory cytokine production (e.g. IL-4, IL-5,
IL-10, and IL-13).
08 FTHC Only low anti-inflammatory activity Epithelial cancer cell lines (A549) [6]
09 FCBD showed reduction of IL-6 and IL-8 secretion levels Epithelial cancer cell lines (A549) [6]
from lung epithelial cells with an IC50 values of
3.45 and 3.49 μg/mL respectively.
7.1. Clinical evaluation of plant-based therapeutics provide supportive therapy against COVID-19 via upregulating levels of
interleukins (IL-1α, IL-1β), monocytes, and lymphocytes in patients [4,
In-depth systemic randomized and non-randomized ongoing clinical 37]. Apart from these, green tea polyphenols can prevent airway
trials of single plant species (Tinospora cordifolia, Nigella sativa, Boswellia blockage by reducing mucin hypersecretion, a phenomenon seen in
serrata, Acai Palm Berry, Caesalpinia spinosa, Cinchona/Stevia, Cannabis COVID-19 patients [81]. Moreover, several plant species act as good
sp, Brazilian Green Propolis), plant-based bioactive compounds (EGCG, source of expectorants as they can elevate the water contents of respi
quercetin, silymarin, hesperidin, escin, colchicine, resveratrol, canna ratory mucus or diluent of mucus and thus also contributing towards
bidiol, melatonin etc.), as well as poly-herbal formulations (ArtemiC, prohibiting airway blockage [26,44].
Drug – ADAPT-232, Dietary supplement: Inflammation-I, Inflammation-
II, Inflammation-III, Tomeka, Shanshamani Vati Plus, Dietary Supple 8. Conclusions
ment: QuadraMune (TM), Ayurvedic formulation, Dietary Supplement:
Cretan IAMA, Individualized-Chinese herbal medicine) showed their Since December 2019, SARS-CoV-2 infection and transmission have
potential to interfere with COVID-19 pathogenesis via inhibiting virus been a huge concern worldwide. Currently available therapies inhibit
replication, virus-mediated pneumonia as well as inmmune dysregula SARS-CoV-2, however, they could be associated with severe side effects
tion such as cytokine storming (Supplementary Table). Certain anti- as well as drug-nutrition interactions which could be harmful to severely
inflammatory herbal medicines from Andrographis paniculata, Citrus infected patients.
spp, and Cuminum cyminum can relieve fever and cough in COVID-19 On other hand, the complementary approach including plant-
patients [37]). Few other medicinal plants such as Glycyrrhiza glabra, derived compounds could be used in controlling COVID-19 in the
Thymus vulgaris, Allium sativum, Althea officinalis, Panax ginseng and future. Our review herein presented a compilation of in-silico, in-vitro,
constituents of Camellia sinensis may modulate the immune system and cell culture , and in-vivo studies on numerous plants, plant formulations,
15
Data availability
Data derived from public domain resources. No new data was used
for the research described in this article.
Acknowledgements
We thank Mayra Segura for proofreading and language editing.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.

org/10.1016/j.micpath.2022.105512.
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Microbial Pathogenesis 168 (2022) 105512

Contents lists available at ScienceDirect

Multifaceted roles of plant derived small molecule inhibitors on replication

infected COVID-19 patients resulting in the unrecognized source of

Abbreviations gRNA genomic RNA

Fig. 3. The life cycle of SARS-CoV-2 and

Fig. 5. Molecular structure of spike pro­

The replication and transcription of the SARS-CoV-2 RNA genome (~

ACE2 (host protein acting as CoV-2 receptor)

TMPRSS2 (host protease)

Furin (host protein)

Class Small molecule inhibitors References

Papain-like protease/nsp3 (viral protease)

3 Chymotrypsin-like protease/nsp5 (viral protease)

RNA dependent RNA polymerase/nsp12 (viral replicase)

Helicase/nsp13 (viral protein)

Endoribonuclease/nsp15 (viral protein)

2′-O- methyl transferase/nsp16 (viral protein)

01 Baicalein 3CLpro - Invitro IC50 0.39 ± 0.11 μM [50]

36 Remidesivir Cytotoxicity Beas-2B cell CC50 >100 [108]

N protein is a 419 amino acid protein with conserved N-terminal

– Prevents the cytokine storm and mucous [81]

We thank Mayra Segura for proofreading and language editing.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.

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Fig. 5. Molecular structure of spike pro