key: cord-0831397-23wvxeec
authors: Uma Reddy, B.; Routhu, Nanda Kishore; Kumar, Anuj
title: Multifaceted role of plant derived small molecule inhibitors on replication cycle of sars-cov-2
date: 2022-04-02
journal: Microb Pathog
DOI: 10.1016/j.micpath.2022.105512
sha: 6eac00454e643a5bf4b28653750e02330621f3ae
doc_id: 831397
cord_uid: 23wvxeec

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an illness caused by the new coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has affected public health and the economy globally. However, no specific antivirals are available, although several are in development. Currently approved vaccines and other drug candidates could be associated with several drawbacks urges to develop alternative therapeutic approaches. AIM: To provide a comprehensive review of anti-SARS-CoV-2 activities of plants and their bioactive compounds. METHODS: Information was gathered from diverse bibliographic platforms such as PubMed, Google scholar, web of science, 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, polyprotein 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-CoV2 infection and anti-viral mechanisms of plant-based therapeutics.

A newly emerged pandemic of COVID-19, caused by an infectious coronavirus SARS-et al., 2020; Armijos-Jaramillo et al., 2020) (Figure-5) . In-silico docking results showed 138 that the phytocompounds enlisted under the spike section in Table-1 Histochemical and single-cell RNA sequencing techniques revealed that ACE2 is 147 primarily expressed in type-II lung alveolar epithelial cells (Hamming et al., 2004; Zhou 148 et al., 2020a) . 149 150 A recent study using bioinformatics, cheminformatics, and molecular docking, has 151 demonstrated that tea flavonoids (epigallocatechin gallate, EGCG, and theaflavin 152 gallate) have higher atomic contact energy value, dissociation constant (Ki)-value, 153 surface area, ligand efficiency, and higher number of amino acid interactions with 154 spike protein than synthetic hydroxychloroquine (Maiti and Banerjee et al., 2020) . 155

Another study showed that daturaolone, gallotannins, taraxerol, tinosporide, 156 withanolide-A, deoxytubulosine, withametelin form strong hydrogen and non-bonding 157 interactions with the amino acids of spike protein (between Arg 403 to Tyr 505) and 158 have drug-likeliness properties based on Lipinski's rule of five. Moreover, these 159 bioactive compounds have lower toxic effects and better gastrointestinal absorption 160 than standards (Mondal et al., 2020) . A simulation study using the crystal structure of 161 SARS-CoV-2 S protein demonstrated that saikosaponin-U and saikosaponin-V, 162 J o u r n a l P r e -p r o o f oleanane derivatives found in Chinese medicinal plants, can also interact with the 163 spike glycoprotein via their octadecahydropicene and oxane rings (Sinha et al., 2021) . 164

Using molecular docking and conceptual density functional theory approaches. 165

Kulkarni et al showed that components of essential oils (monoterpenes, terpenoid 166 phenols and phenyl propanoids) have the potential to interact with the RBD domain 167 (Kulkarni et al., 2020) . The phytocompounds punicalagin and punicalin (from 168 Pomegranate), tenufolin, cinnamtannin-B1, pavetannin-C1, 6-glucopyranosyl 169 procyanidin B1, procyanidin-B7, proanthocyanidin-A2 and Kaempferol-3-alpha-L-170 arabinoside-7-rhamnoside (from Cinnamon), frieldlin, and stigmasterol (from 171

Clerodendrum spp) were also found to be effective candidates exhibiting important 172 interactions with the targeted spike protein Prasanth et al., 2020; 173 Suručić et al., 2021a) , suggesting that they could serve as possible candidates for 174 further in-vitro and in-vivo evaluations. Additionally, a molecular dynamics simulation 175 study of the complex of RBD of S-protein with taraxerol for a time scale of 40 176 nanoseconds revealed its potent anti-SARS-CoV-2 activity . 177

traditional medicine demonstrated stable intramolecular interactions with Asn343, 179 which could be an important hit to affect host-immune evasion by inhibiting S-protein 180 glycosylation (Umashankar et al., 2021) . 181

The complex between viral S protein and human ACE2 has also been explored to 182 identify antiviral phytochemicals. Using molecular dynamics, hesperidin, a major 183 flavonoid present in citrus fruits, has been demonstrated to interact with this complex 184 noncompetitively at a site different from that of S-protein. Further, the antiviral activity 185 of hesperidin was validated by a quantitative structure-activity relationship study (Basu 186 et al., 2020) . Another study, using virtual screening followed by protein-ligand 187 J o u r n a l P r e -p r o o f interaction approach, showed that phytochemicals like glycyrrhizinic acid, maslinic 188 acid, ursolic acid, corosolic acid, 2-hydroxyseneganolide, gedunin, and oleanane can 189 bind firmly with the active site and other important amino residues of S protein and 190 ACE2 through multiple noncovalent interactions (Vardhan and Sahoo, 2020) . Of 191 interest, His-34 is an important amino acid of ACE2 receptor as it lies on the surface 192 and exhibits interactions with the S protein. One of the molecular dynamic studies 193 revealed that the andrographolide and pterostilbene could negatively affect CoV-2 by interacting with His-34 (Alazmi and Motwalli, 2020) . Rilapladib, a quinoline, 195 can interrupt the spike-ACE2 complex (Alexpandi et al., 2020) . Natural compounds 196 such as isothymol, thymol, p-cymene, limonene, and gamma-terpinene (from 197 Ammoides verticillata), and 17-organosulfur compounds (from garlic) were also found 198 to be potential inhibitors of ACE2 receptor (Abdelli et al., 2021; Thuy et al., 2020). 199 Further, xanthones, proanthocyanidins, secoiridoids, naringenin, hesperetin, baicalin 200 and neohesperidin, scutellarin, nicotinamin, and glycyrinodin could exhibit ACE2 201 inhibition activity (Muchtaridi et al., 2020) . Hesperidin can modulate the binding energy 202 of ACE2-spike protein complex and affects the stability of viral-host interaction (Basu 203 et al., 2020) . At the binding contact of the spike-ACE2 complex, the di-hydroflavone 204 moiety of hesperidin has been predicted to be parallel to the β-6 sheet of RBD (Wu et 205 al., 2020) . Apart from this, punicalin and punicalagin from pomegranate peel are 206 predicted to interact with ACE2 and block entry of SARS-CoV-2 into host cells (Suručić 207 et al., 2021a) . Several bioactive compounds can interact with hot-spot binding 208 residues (Lys31 and Lys353) of the ACE2 receptor through hydrogen bond or non-209 bonded interactions (Mondal et al., 2020) . Besides these, geranium and lemon 210 essential oils downregulate the expression of ACE2 in human colon adenocarcinoma 211 cells as observed by western blot experiments (Kumar et al., 2020a) . More details of 212 J o u r n a l P r e -p r o o f Another study recommended certain compounds such as catechin, naringenin, 287 kaempferol, glucosides, quercetin, and epicatechin-gallate as potential inhibitors of 288 3CLpro (Khaerunnisa et al., 2020) . The phytocompounds like melitric acid-A, 289 salvianolic acid-A, withanoside-V, and a few bioactive compounds from Calendula 290 officinalis showed higher binding affinities with 3-CLpro than the N3 and lopinavir 291 (standards). Also, they could have important interactions with the amino acid residues 292 of the catalytic dyad Elekofehinti et al., 2020; Mondal et al., 2020; 293 Tripathi et al., 2020; Das et al., 2020) . In another study, a database of medicinal plants 294

consisting of more than 30,000 potential anti-viral phytochemicals was screened, and 295 the top hits that could inhibit SARS-CoV-2 3CLpro function and viral RNA replication 296 were selected. These hits include myricitrin, 5,7,3',4'-tetrahydroxy2'- (3,3- 3,5,7,3',4',5'-hexahydroxy flavanone-3-O-beta-299 D-glucopyranoside, myricetin 3-O-beta-D-glucopyranoside, licoleafol, amaranthine, 300 colistin, nelfinavir, and prulifloxacin (Qamar et al., 2020) . Terpenoids Oxoisoiguesterin and 22-hydroxyhopan-3-one) and some anthocyanin derivatives 302 could stably interact with catalytic dyad and other crucial residues via hydrogen and 303 hydrophobic interactions (Fakhar et al., 2020; Gyebi et al., 2021) .Epigallocatechin, 304 gallocatechin, epicatechin from green tea also showed the potential to restrict the 305 activity of 3-CL pro (Ghosh et al., 2020) . Similarly, several phytocompounds binds 306 firmly at catalytic dyad (Cys-145 and His-41) and other crucial amino acid residues 307 (Phe-140, 308 Leu-167, Pro-168, His-172, Asp-187, Arg-188) of 3-CL pro via making hydrogen, 309 hydrophobic bonding and other interactions (like Pi-alkyl and Pi-Pi T-shaped, Vander 310 Waals etc). Phytocompounds extracted from Avincennia officinalis and Iranian 311 medicinal plants have also been proposed as inhibitors of 3-CLpro (Mahmud et al., 312 2021; . Tanshinones, a class of natural phytocompounds have 313 been found to inhibit 3-CLpro activity of SARS-CoV in-vitro enzymatic assay studies 314 (Park et al., 2012) . Likewise, as listed in Table-1 withanoside-X, and dihydrowithaferin-A from Withania somnifera could potentially 357 suppress the nsp15 endoribonuclease activity of SARS-CoV2 (Chikhale et al., 2020b) . 358

Another study revealed the binding capacity of silymarin, sarsasapogenin, ursonic 359 acid, rosmarinic acid, curcumin, ajmalicine, novobiocin, aranotin, gingerol, and alpha 360 terpinyl acetate to nsp15 protein ) 361 362 5.6 2'-O-methyltransferase (2′-O-MTase)/nsp16: This is a highly conserved protein 363 of coronaviruses. It is known to play an essential role in viral replication and evasion 364 of host cell innate immunity (Paramasivam, 2020) . Phytocompounds like eryvarin-M, 365 osajin, raddeanine, and silydianin have been found to exhibit the best docking results 366 (Table-1) . 367 368

Structural proteins, membrane, envelope and nucleocapsid, play essential roles in the 370 assembly and formation of the infectious virion particles. Therefore, targeting these 371 proteins could be a promising approach to inhibit virus multiplication and transmission. 372 and efficient replication. The NC protein is highly immunogenic and is produced in high 383 amounts during infection (Zhou et al., 2020b; Ding et al., 2016) . 384 shiraiachrome A, resveratrol, and baicalein. Moreover, Ginkgolic acid is a specific 410 covalent inhibitor of SARS-CoV-2 cysteine proteases, targeting PLpro and 3-CLpro in-411 vitro (Yang et al., 2021, and Chen et al., 2021) (Table 2 and 3) . 412

In another study, 122 Thai natural products for anti-SARS-CoV-2 activity were 413 screened using fluorescence-based nucleoprotein detection combined with viral 414 plaque reduction assay. This work showed that the extract of Boesenbergia rotunda 415 and its phytochemical compound, panduratin A reduce SARS-CoV-2 infectivity in Vero 416 E6 cells at pre-entry and post-infection phases (Kanjanasirirat et al., 2020) . Artemisinin 417 B, an antimalarial drug derived from Chinese herbs, also showed anti-SARS-CoV-2 in 418 these cells by blocking SARS-CoV-2 at the post-entry level (Cao et al., 2020c) . In another study, Glycyrrhizin showed potential antiviral activity against SARS-CoV-2 425 by inhibiting the viral 3-CL pro that is essential for viral replication (van de sand et al., 426 2021) . Similarly, several other plant-derived compounds including tea polyphenols 427 EGCG, theaflavin, baicalein, and shuanghuanglian inhibit 3-CLpro activity and the viral 428 replication in Vero E6 cell line (Jang et al., 2020 , Su et al., 2020 Liu et al., 2021) . concern worldwide. Currently, available therapies inhibit SARS-CoV2, however, they 462 could be associated with severe side effects as well as drug-nutrition interactions 463 which could be harmful to severely infected patients. , artemisinin (4 IR and -6.2 BE), tinosporide (2HB, 6-NBI and -6.4 BE), andrographolide (6 IR and -9.1 BE), taraxerol (7-NBI and -7.9 BE), daturaolone (8 NBI and -7.5 BE), glycyrrhizin (7-HB, 3-NBI, -7.1 BE), friedelin (1-HB, 2-IR and -7.3 BE), tenuifolin (4-HB, 2-HP and -8.7 BE), ϒ-terpinene , αterpinene .0 BE), ϒterpinene Pavetannin-C1 (9-HB, 4-HP, 1-EI and -11.1 BE), hesperidin (5 IR and -8.99), chrysin (9 IR and -6.87), querceitin 3-O-robinobioside (5-HB, 6-NBI, -7.9 BE), kaempferol 3 -alpha-Larabinofuranoside 7-rhamnoside (7-HB, 2-HP and -8.7 BE), catechin gallate (5 HB, 3 HP and -6.1 BE), cinnamaldehyde Oleonolic acid (4 IR and -10 BE), ursolic acid (5 IR and -9.7 BE), 3βacetoxyolean-12-en-27-ioc acid Sharma et al., 2020 Beta-hydroxy ketone Zingerol (5 IR and -5.40 BE) and gingerol Met49, His163, Met165, Glu166, Pro168, Asp187, Arg188, Gln189, Thr190 Khaerunnisa,et al., 2020 Furanocoumarin Bergapten (5methoxypsoralens) Phe140, His163 Sharma et al., 2020 Anthocyanins Delphinidin 3-Sambubioside-5-Glucoside (27 IR and -12.37 BE); Thr24, Thr25, Thr26, Leu27, His41, Cys44, Met49, Leu50, Pro52, Tyr54, Gly138, Ser139, Phe140, Leu141, Fakhar et al., 2020 J o u r n a l P r e -p r o o f .30 BE),

[3,4,5trihydroxy-6-(hydroxymethyl)oxan-2yl]oxy>-1lambda-chromen-1-ylium , Cyanidin 3-(60 '-pcoumarylsambubioside) (22 and -9.58 BE),

Aromatic alcohol and -7.9 BE), tinosporide (2 HB, , chebulagic acid (6 HB, , chebulinic acid (9 HB, 9 NBI and -8.6 BE), gallotannins (5 HB, 10 NBI and -8.3 BE), cinnamtannin-B1 (3 HB, , barlerinoside (7 HB, 10 NBI and -7.5 BE) Hydroxycinnamic acid (3 HB, 2A, 1 PA, Phenethyl alcohol (6 HB, 2 PA, -5.6 BE), ricinoleic acid (3) (4) (5) .0 BE), alpha asarone , valproic acid Organosulfur allicin His235, Thr341, His250 Kumar et al., 2021 Alkaloid Taspine (4 IR and -7.3 BE), ajmalicine (5 IR and -8.1 BE), reserpine (4 IR and -7.4) His235, Thr341, Gly248, His250, Lys290, Glu340 Kumar et al., 2021 Steroids Asparoside-C (5 HB and -7.16 BE), asparoside-F (7 HB and -6.6 BE), asparoside-D J o u r n a l P r e -p r o o f 

High-content screening of Thai medicinal plants 681 reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS

CoV-2 agents

Potential inhibitor 685 of COVID-19 main protease (Mpro) from several medicinal plant compounds by 686 molecular docking study

Srivastava 690 S. Cytokine storm and mucus hypersecretion in COVID-19: Review of Mechanisms

Structure of the SARS-CoV NSP12 polymerase bound to 694 NSP7 and NSP8 co-factors

Phytochemicals from selective 698 plants have promising potential against SARS-CoV-2: Investigation and corroboration 699 through molecular docking, MD simulations, and quantum computations

703 Computational evaluation of major components from plant essential oils as potent 704 inhibitors of SARS-CoV-2 spike protein

Geranium and lemon essential oils and their active compounds 709 downregulate angiotensin-converting enzyme 2 (ACE2), a SARS-CoV-2 spike 710 receptor-binding domain, in epithelial cells

Withanone and withaferin-A are predicted to interact with transmembrane 715 protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells

Struct Dyn 2020b

Scutellaria 718 baicalensis extract and baicalin inhibit replication of SARS CoV-2 and its 3C -like 719 protease in-vitro

-HB, 3-HP, 2-EI and -9.6 BE), proanthocyanidin-A2 (5-HxB, 1-HP, 2-EI and -9.4 BE), ellagic acid (3 IR and -6.114 BE)

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

Tannins Punicalin (5 IR and -7.353 BE), punicalagin (4 IR and -7.144 BE), ellagic acid (4 IR and -6.85 BE), gallic acid (4 IR and -5.24 BE), pedunculagin (4 HB, 4 HPI and -7.2 BE)

Flavonoid Hesperidin (4 IR and -9.167 BE), chrysin (3 IR and -7.146 BE), rutin (6 IR and -3.41 BE), vitexin (7 IR and -5.71 BE), apigenin (5 IR and -3.75 BE)

Quinone Emodin (3 IR and -9.83 BE)

IR and -2.75 BE), carvacrol (7 IR and -3.31 BE), costunolide (4 IR and -4.0 BE), cynaropicrin (5 IR and -3.06 BE), bharangin (4 IR and -4.36 BE), andrographolide (6 IR and -4.53 BE), beta-pinene (5 IR and -5.22 BE), spathulenol (6 IR and -4.98 BE), vetiverol ( 6 IR and -4.96 BE), cucurbitacin B (6 IR and -5.36 BE), alpha-bisabolol (7 IR and -5.69 BE), 6-shogaol (6 IR and -3.33 BE), 6-gingerol (6 IR and -3.49 BE)

5 BE), maslinic acid (4 HB, 3 Pi-Alkyl, 5 VDW and -8.5 BE), obacunone (1 HB, 1 Pisigma, 1 Pi-Pi T shaped, 2 Pi-Alkyl, 8 VSW and -8.1 BE), epoxyazadiradione

Ursolic acid (3 HB, 3 Pi-Alkyl, 7 VDW and -7.4 BE), gedunin (1 HB, 3 Alkyl/ Pi-Alkyl, 1 Pi

Alkaloids Pellitorine (5 IR and -3.4 BE), vasicine (5 IR and -6.21 BE), piperidine (9 IR and -4.31 BE)

Standards Lopinavir (9 IR and -7.5 BE), umifenovir (7 IR and -6.5 BE)

catechin gallate (6 IR and -7.2 BE), epigallocatechin gallate (9 IR and -7.6 BE), epicatechin gallate (10 IR and -8.2 BE), gallocatechin-3-gallate (9 IR and -9.0 BE), kaempferol (4 HB, 6 HPI and -8.58 BE), quercetin (8 IR and -6.58), luteolin-7-glucoside (10 IR and -8.17 BE), myricetin (4 IR and -6.15 BE), scutellarin (2 IR and -7.13 BE), isoflavone (2 IR and -5.69 BE)

quercetin-7-Osulfate (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 and -8.1 BE), quercetin (4 HB; 1 PS, 2 Pal and -7.5 BE)

HB, 4 IR and -9.1 BE), daturaolone (10 NBI and

2 BE), calendulaglycoside B (16 IR and -8.2 BE), calenduloside (15 IR

8 BE), 7-Deacetyl-7-benzoylgedunin L

Obacunone (3 HB, 1 pi-donor, 1 pi-alkyl, 5 VDW

Sesquiterpene Badrakemin acetate (2 HB, 5 HP and -8.6 BE), Samarcandin (3 HB, 2 HP and -8.5 BE)

Cyanidin 3,5-di-Oglucoside (4 HB, 6 HP and

Cyanidin 3-Orutinoside (7 HB, 4 HP and

Steroidal lactone Withanoside-II (20 IR and -11.30 BE), withanoside IV (20 IR and 11.02 BE), withanoside-V (27 IR and -8.96 BE), sitoindoside IX (24 IR and -8.37 BE

N-[(5-methylisoxazole -3-yl) carbonyl] alanyl-l-valyl-n1-((1r,2z)-4-(benzyloxy) -4 -oxo -1-[(3r)-2-oxopyrrolidin-3-yl] methyl] but-2-enyl)-l-leucinamide (3 HB, 3 HPI

Tannins Pedunculagin (5 HB, 9 NBI and -8.9 BE), punigluconin (6 HB, 12 NBI and -8.5 BE), taraxerol (11 NBI and -7.2 BE), withametelin (8 NBI Thr24

HB, 6 HPI and -7.9 BE/ 28 IR and

BE/ 23 IR and -8.12 BE), nelfinavir

4 BE), ribavirin (5 IR and -5.43 BE), lopinavir (3 HB, 3 HP and -9.41 BE), ritonavir (2 HB, 3 IR and -6.8 BE)

RNA dependent RNA polymerase / nsp12 (viral replicase) Class Small molecule inhibitors Interacting residues with different classes of phytocompounds References Flavonoid Theaflavin (8 HB, 2 PA and -9.1 BE), quercetin-3-O-(rutin) (9 HB, 1 Psi and -8.5 BE)

BE), quercetin-7-O-sulfate ( 6 HB, 1 PC

HB, 1 PC, 1 Pal and -8.1 BE), quercetin (3 HB, 2 Psi and -7.4 BE), kaempferol-3-Orutinose (4 HB, 2 PA and -9.2 BE), kaempferol -4'-O-glucuronide (6 HB, 1 PC and -8.3 BE), kaempferol-3-O-glucuronide

Terpenoids Glycyrrhizic acid (7 HB, 1 CHB, 1 pi-alkyl, 16 VDW and -9.9 BE), limonin (2 HB, 2 pi-alkyl, 1 pi-pi T shaped, 10 VDW and -8.2 BE)

Alkyl/ pi-alkyl, 2 CHB, 1 pi-anion, 3 pi-cation, 6 VDW and -8.2 BE)

HB, 2 CHB, 1 Pi-Alkyl, 1 Pi-sigma, 1 Pianion, 5 VDW and -8.1 BE), obacunone (2 HB, 1 Alkyl, 1 Pi-Anion, 8 VDW

Standards Remdesivir (3 IR and -6.3 BE), favipiravir (3 IR and -3.6 BE)

osajin (4 IR and -8.2 BE), sesquiterpene glycoside (9 IR and -8.2 BE), rhamnetin (9 IR and -8.1 BE), silydianin

Standards Nelfinavir (6 IR and -6.2 BE), remdesivir (8 IR and -6.8 BE), prulifloxacin (7 IR and -8.1 BE) References Flavonoid Quercetin-3-O-galactosyl-rhamnosylglucoside (3 HB and -6.7 BE), naringin (5 IR and -7.8 BE), taxifolin (6 IR and -7.2 BE), luteolin (5 IR and -7.2 BE), apigenin (4 IR and -7.2 BE), myricetin (4 IR and -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)

Betadiketone Demethoxycurcumin (5 IR and -7.51 BE), quercetin (4 IR and -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), remdesivir (1 IR

27 BE), saikosaponin-C (6 HB, 9 HP and -6.98 BE), saikosaponin-K (5 HB, 10 HP and -6.79 BE), saikosaponin-1b (4 HB, 8 HP and -6.36 BE), alpha-amyrin (1 IR and -8.1 BE), pomolic acid

carinatine (4 IR and -6.6 BE), 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 His235

References Flavonoids, Alkaloids, others Eryvarin-M (9 IR and -8.6 BE), silydianin (9 IR and -8.5), osajin (6 IR and -8.2 BE), raddeanine

Standards Nelfinavir (9 IR and -8.2 BE), remdesivir (9 IR and -7.0 BE)

EI-electrostatic interactions, CHB -carbon-hydrogen bond, VDW -van der Waals interactions. PS: π-sulfur

Psi: π-sigma

Affect the release of TNF-α, IL-1α, IL-1β, IL-5, IL-3, IL-6, IL-8, IP-10, IL-12p70, IL-13, IL-18, CCL2, MCP-1

Furin cleavage site

Other phytocompounds

Phytocompounds affect the crucial steps of SARS-CoV-2 infection cycle. 2. Phytocompounds display strong affinities to the key viral enzymes. 3. These molecules also exhibit greater stability and a higher safety profile 4

and -8.0 BE), kaempferol-3-O-glucuronide (6 HB, 1 PS, 1 PP, , kaempferol-7-Oglucuronide (4 HB, 2 PS, 1 Psi, 2 Pal and -8.3 BE), kaempferol-7-O-sulfate (3 HB, 1 PS, 1 PP, , kaempferol-4'-Osulfate (4 HB, 1 Pal and -8.2 BE), kaempferol-3-Osulfate (3 HB, 1 PS, , kaempferol (1 HB, 2 PS, , 5,7,3'4' -tetrahydroxy2'-(3,3dimethylallyl) isoflavone , myricitrin , methyl rosmarinate .44 BE), 3,5,7,3',4',5'hexahydroxy flavanone -3 -Obeta -D glucopyranoside , (2S)-eriodictyol 7-O-(6''-Ogalloyl)-beta-Dglucopyranoside, , 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-Oglucoside (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) -7methoxy -5 -[(6 -Ob -Dxylopyranosylb -Dglucopyranosyl) 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-J o u r n a l P r e -p r o o f L-arabinopyranoside (4 HB, 6 IR and -9.0 BE), kaempferol 3-rutinoside 40-glucoside (9 HB, 6 HP and -8.9 BE), quercetin 3-O-(6"-O-malonyl)-b-Dglucoside (3 HB, , idaein (2 HB and 8 HP) , callistephin (3 HB and 8 HP) ; malvin (4 HB, 8 HP and -8.7 BE), luteolin 7rutinoside (2 HB; 9 HP; -8.6 BE), cyanin (4 HB; 4 HP; -8.5 BE), kaempferol 7-Oneohesperidoside (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-Lrhamnopyranosylisovitexin (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-Larabinofuranoside-7rhamnoside (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-Orobinobioside (6 HB, , Catechin gallate (7 HB, 4 HP and -8.6 BE), Astragalin (4 HB, 5 HP and -7.9 BE), Rutin (6HB, 3HP and -7.4 BE), Kaempferitrin (5 HB, ATP-stimulated monocyte-derived THP-1 cells also mouse and human islet cellsinvitro. 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 interacted by different groups of plant-based inhibitors (steroids, quinones, terpenoids, flavonoids, and tannins) are also shown. Please refer