Table 2.
Summary of studies with in silico method that used natural products for novel drug discovery against COVID-19.
| Author | Year | Method | Detail of method | Name of compound/drug | Target | Efficacy | Comments |
|---|---|---|---|---|---|---|---|
| Abdelli et al. [120] | 2021 | In silico | Molecular docking | Isothymol, thymol, limonene, P-cymene, and γ-terpinene derived from the essential oil of the antiviral and antimicrobial plant Ammoides verticillata (Desf.) Briq. | Inhibition of ACE2 cellular receptor | Isothymol, a major component of this plant, gives the best docking scores, as good ACE2 inhibitor | |
| Abouelela et al. [121] | 2021 | In silico | Molecular docking, dynamic simulation, and binding free energy calculation | Aloe | Main protease and spike protein | 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamic simulation | |
| Adem et al. [122] | 2020 | In silico | Molecular docking | Medicinal plant-based bioactive compounds (80 flavonoid compounds) | Main protease | Hesperidin, rutin, diosmin, apiin, diacetylcurcumin, (E)-1-(2-hydroxy-4-methoxyphenyl)-3-[3-[(E)-3-(2-hydroxy-4-methoxyphenyl)-3-oxoprop-1-enyl]phenyl]prop-2-en-1-one, and beta, beta′-(4-methoxy-1,3-phenylene)bis(2′-hydroxy-4′,6′-dimethoxyacrylophenone have been found as more effective on COVID-19 than nelfinavir | |
| Allam et al. [123] | 2020 | In silico | Molecular docking, 3D shape similarity study (rapid overlay chemical similarity-ROCS) to the clinically used drugs in COVID-19 patients | 3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4, ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, which were isolated from peach (Prunus persica (L.) Batsch) fruits | Main protease, spike protein | Naringenin 2 and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3 have a strong binding mode to a protease receptor and spike protein and also block the inflammatory storm | Recommendation of peach fruits in controlling and managing COVID-19 cases |
| Al‐Sehemi et al. [124] | 2020 | In silico | Molecular docking | 31000 natural compounds of the natural product activity and species source (NPASS) library | Spike glycoprotein | Castanospermine and karuquinone B were shown to be the best-in-class derivatives in silico able to target an essential structure of the virus and to act in the early stage of infection | |
| Attia et al. [125] | 2021 | In silico | Molecular docking | 10 phenolic antiviral | Against SARS-CoV-2 | Hesperidin showed the highest docking score | Hesperidin and its mediated ZnO nanoparticles are willing antiviral agents |
| Azim et al. [126] | 2020 | In silico | Virtual screening methods molecular docking | 27 plant metabolites | Main protease proteins (MPP), Nsp9 RNA-binding protein, spike receptor-binding domain, spike ectodomain, and HR2 domain | Asiatic acid, avicularin, guajaverin, and withaferin showed a maximum binding affinity with all key proteins in terms of lowest global binding energy | |
| Bhowmik et al. [39] | 2021 | In silico | Repurposing drugs, docking, and molecular dynamic simulation | Orientin (phytochemical) | Inhibitor of SARS-CoV-2 spike and host cell receptor GRP78 binding | Binding of orientin in the overlapping residues of GRP78 binding region of SARS-CoV-2 spike model | As a promising precautionary or therapeutic measure for COVID-19 |
| Çakır et al. [127] | 2021 | In silico | Molecular docking | Peptides derived from beta-lactoglobulin | Inhibit the host cell membrane receptors | Ala-Leu-Pro-Met-His-Ile-Arg (ALMPHIR) and Ile-Pro-Ala-Val-Phe-Lys (IPAVFK) peptides | β-Lactoglobulin (BLG) is the major whey protein of cow and sheep's milk (∼3 g/l) |
| Chatterjee et al. [128] | 2021 | In silico | Molecular docking | Hesperidin, kaempferol, quercetin, epigallocatechin | PLpro (papain-like protease), RdRp (RNA-dependent RNA polymerase), Mpro or 3cl protease, and spike protein | Hesperidin, kaempferol, quercetin, epigallocatechin | Lead to conclusive data for the treatment of polyphenols, flavonoids, and bioflavonoids against SARS-CoV-2 |
| Chikhale et al. [129] | 2020 | In silico | Molecular docking, dynamics | Plant Withania somnifera (Indian ginseng) | NSP15 endoribonuclease and receptor-binding domain of prefusion spike protein | Withanoside X and quercetin glucoside from W. somnifera have favorable interactions at the binding site of selected proteins | Immunomodulatory, antioxidant, and anti-inflammatory roles |
| Chikhale et al. [130] | 2021 | In silico | Molecular docking, dynamics, and network pharmacology analysis | Saikosaponins | Adjuvant therapy in the treatment of COVID-19 | Saikosaponins interact with the proteins CAT gene CAT (catalase) and checkpoint kinase 1 (CHEK1) | Possible improvement in immune response towards COVID-19 |
| Chikhalet al. [131] | 2020 | In silico | Molecular docking, dynamics | Asparagus racemosus (Willd.) | NSP15 endoribonuclease and spike receptor-binding domain | Asparoside -C and Asparoside -F have good binding with target proteins | Asparagus racemosus holds promise as SARS-CoV-2 (S) and (N) protein inhibitor |
| Chowdhury [132] | 2020 | In silico | Molecular docking, dynamics | Tinospora cordifolia (Giloy) | Main protease | Berberine can regulate main protease protein's function | |
| Dahab et al. [133] | 2020 | In silico | Molecular docking | 10 phenolic compounds of different classes (phenolic acids, flavonoids, and coumarins) | Main protease and RNA polymerase | The top 7 hits are flacourticin [3], sagerinic acid [16], hordatine a [23], hordatine B [134], N-feruloyl tyramine dimer [135], bisavenanthramides B-5 [27], and vulnibactins [38] and have better binding scores than remdesivir, the native ligand in RNA polymerase target (PDB ID: 7bV2) | Hordatines are phenolic compounds present in barley and were found to exhibit the highest binding affinity to both protease and polymerase |
| Das et al. [136] | 2020 | In silico | Molecular docking | Flavonoid-based phytochemicals of Calendula officinalis | Main protease | Rutin, isorhamnetin-3-O-β-D, calendoflaside, narcissin, calendulaglycoside B, calenduloside, and calendoflavoside have better binding energy than the native ligand | Rutin and caledoflaside showed better stability, compactness, and flexibility |
| Debnath et al. [137] | 2020 | In silico | Sequential E-pharmacophore and structure-based virtual screening (VS) | 113687 number of commercially available natural compounds | ADP-ribose phosphatase | 6 potential inhibitors having good binding affinity towards active sites | Commercially available |
| Dev and Kaur [138] | 2020 | In silico | Molecular docking | Eucalyptus essential oil | Main protease | Jensenone may represent potential treatment potential to act as main protease inhibitor | |
| Duru et al. [139] | 2021 | In silico | Molecular docking | Oil of Nigella sativa seed | Replicase polyprotein 1a, RNA-binding protein of NSP9, ADP ribose phosphatase of NSP3, 3-chymotrypsin-like protease 3CLpro, and RNA-dependent RNA polymerase RdRp, and ACE2-angiotensin-converting enzyme from the Homo sapiens | The binding affinity of caryophyllene oxide was the highest on NSP9 and RdRp targets, while α-bergamotene gave the best binding affinity on RPIA target. The binding affinity of β-bisabolene on the ACE2 was almost the same as remdesivir | |
| El-Demerdash et al. [140] | 2021 | In silico | Molecular dynamic simulations, molecular docking | 15 guanidine alkaloids | Main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a nonstructural protein (nsp10) (PDB ID: 6W4H) | Crambescidin 786 [5] and crambescidin 826 had the highest binding affinities. The examined 15 alkaloids especially 5 and 13 showed promising docking, ADMET, toxicity, and MD results | |
| Elekofehinti et al. [141] | 2020 | In silico | Molecular docking studies, molecular dynamics, and ADME/Tox | 50,000 natural compounds retrieved from IBS database | Papain-like protease | STOCK1N-69160 [(S)-2-((R)-4-((R)-2-amino-3-methylbutanamido)-3-(4-chlorophenyl) butanamido)propanoic acid hydrochloride] has been proposed as a novel inhibitor against COVID-19 PLpro | |
| El‐Hawary et al. [142] | 2021 | In silico | Molecular docking (a combination of metabolomics and in silico approaches) | A. terreus, the endophytic fungus associated with soybean roots | Main protease | Aspergillide B1 and 3α-hydroxy-3,5-dihydromonacolin L were found to be potent anti-COVID-19 drug candidates | |
| Emirik [143] | 2020 | In silico | Molecular docking, MM-GBSA-based predictions, and molecular dynamics | Turmeric contents | SARS-CoV-2 vital proteins | Turmeric spice has the potential to inhibit the SARS-CoV-2 vital proteins and can be used a therapeutic or protective agent against SARS-CoV-2 via inhibiting key protein of the SARS-CoV-2. Compounds 4, 23, and 6 are the most prominent inhibitor for the main protease, the spike glycoprotein, and RNA polymerase of virus, respectively | |
| Fakhar et al. [144] | 2020 | In silico | Structure-based pharmacophore modeling, virtual screening-based PHASE screen score, molecular modeling | Anthocyanin derivatives | Main protease | 6 best anthocyanin-derived natural compounds, which could be used as promising lead compounds against main protease SARS-CoV-2 | |
| Falade et al. [145] | 2021 | In silico | Molecular docking | Saponins and tannins | Main protease | Ellagic acid, arjunic acid, theasapogenol B, and euscaphic acid as potential inhibitors of SARS-CoV-2 (Mpro) with better pharmacokinetics and bioavailability compared with remdesivir | |
| Fitriani et al. [146] | 2020 | In silico | Molecular docking | Phytochemical compounds (Moringa oleifera, Allium cepa, Cocos nucifera, Psidium guajava, and Eucalyptus globulus) | Main protease | Oleanolic acid in Allium cepa, α-tocotrienol in Cocos nucifera, asiatic acid in Psidium guajava, and culinoside in Eucalyptus globulus were the most recommended compound in each medicinal plant | Oleanolic acid in Allium cepa found as a potential inhibitor of COVID-19 Mpro |
| Gangadevi et al. [147] | 2021 | In silico | Molecular dynamic simulations, molecular docking | Library of natural compounds | Host ACE2 receptor with spike RBD domain of SARS-CoV-2 | Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19 | |
| Gangarapu et al. [148] | 2020 | In silico | Molecular docking online pkCSM and SwissADME Web server | Phytoconstituents of Siddha official formulation kabasura kudineer and novel herbal preparation—JACOM | Spike protein | 37 compounds were screened, and of these, 9 compounds showed high binding affinity against spike protein | SNACK-V formulations could be used for effective treatment of COVID-19 |
| Ghosh et al. [149] | 2020 | In silico | Molecular dynamic simulations, molecular docking | 8 polyphenols from green tea | Main protease | 3 polyphenols (epigallocatechin gallate, epicatechin gallate, and gallocatechin-3-gallate) interact strongly with one or both catalytic residues (His41 and Cys145) of main protease | |
| Ghosh et al. [150] | 2021 | In silico | Molecular dynamic simulations, molecular docking, MM-GBSA analysis | Justicia adhatoda alkaloids | Main protease | 1 alkaloid (anisotine) had interaction with both the catalytic residues (His41 and Cys145) of Mpro and exhibited good binding affinity (−7.9 kcal/mol) | More potent Mpro inhibitor than the two previously recommended antiviral drugs (lopinavir and darunavir) |
| Gorla et al. [151] | 2020 | In silico | Molecular docking | Essential flavonoids | SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD-S) and host angiotensin-converting enzyme-2 protease domain (PD-ACE2) | Biochanin A and silymarin bind significantly at the active sites of RBD-Sand PD-ACE2 | |
| Gurung et al. [152] | 2020 | In silico | Virtual screening, molecular docking | Antiviral compounds from plants | Main protease | Bonducellpin D was identified as the best lead molecule, which shows higher binding affinity | |
| Gyebi et al. [153] | 2021 | In silico | Molecular docking, ADME/Tox, and Lipinski filter analysis | African plants derived alkaloids and terpenoids | Main protease | 4 nontoxic, druggable plant-derived alkaloids (10-hydroxyusambarensine and cryptoquindoline) and terpenoids (6-oxoisoiguesterin and 22-hydroxyhopan-3-one) | |
| Elwakil et al. [154] | 2021 | In silico | Gas chromatography/mass spectrometry analysis molecular docking | Egyptian propolis | RNA-dependent RNA polymerase, spike protein S1, and main protease | Octatriacontyl pentafluoropropionate is well oriented inside the enzyme pockets, in addition to an excellent binding manner with the active site of the target macromolecules | Menoufia propolis could be a promising candidate in the combat against the pandemic COVID-19 |
| Hasan et al. [155] | 2020 | In silico | Molecular docking | Compounds present in the plant Solanum surattense | Main protease | 13 phytochemicals were studied, eight showed very strong binding affinities to main protease, and four showed moderate to strong binding affinities | |
| Hashem [156] | 2020 | In silico | Molecular docking | Honeybee and propolis | Main protease | 6 main compounds possess high binding energy with the receptor active site of the main protease | |
| Ibrahim et al. [157] | 2020 | In silico | Molecular dynamic simulations, molecular docking, MM-GBSA analysis | MolPort database that contains over 100,000 natural products | Main protease | 9 potent natural products with binding affinities (ΔG binding) >−48.0 kcal/mol four bis([1, 3]dioxolo)pyran-5-carboxamide derivatives were identified as potential drug candidates | MolPort-004-849-765, MolPort-000-708-794, MolPort-002-513-915 and MolPort-000-702-646 are bis([1,3]dioxolo)pyran-5-carboxamide derivatives |
| Ibrahim et al. [158] | 2020 | In silico | Molecular dynamic simulations, molecular docking | Metabolites present in several common spices | Main protease | High potency of salvianolic acid A and curcumin as main protease inhibitors | Salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease |
| Isa et al. [159] | 2020 | In silico | Docking and molecular dynamic (MD) simulation | Extracts of Zingiber officinale and Anacardium occidentale | Main protease | Six compounds had good binding energies. CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals | |
| Istifli et al. [160] | 2020 | In silico | Molecular dynamics and molecular mechanic Poisson–Boltzmann surface area (MM/PBSA) methods | 23 phytochemicals belonging to different flavonoid subgroups | Spike glycoprotein cellular proteases (transmembrane serine protease 2 (TMPRSS2), cathepsin B and L (CatB/L)). | (−)-Epicatechin gallate interacted strongly with all the proteins studied | Epicatechin gallate can be evaluated as a candidate molecule in drug development studies against 2019-nCoV since it was not the substrate of P-gp (P-glycoprotein), did not inhibit any of the cytochrome Ps, and did not show AMES toxicity or hepatotoxicity on eukaryotic cells |
| Jan et al. [161] | 2021 | In silico | Cell-based infection assay molecular modeling | 2,855 small molecules and 190 traditional herbal medicines | Main protease RNA-dependent RNA polymerase | Mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, Mentha haplocalyx | |
| Jo et al. [162] | 2020 | In silico | Docking | Flavonoids | Main protease | Baicalin, herbacetin, and pectolinarin have been discovered to block the proteolytic activity. Baicalin showed an effective inhibitory activity against main protease | |
| Joshi et al. [163] | 2021 | In silico | Docking | 7100 molecules | Main protease | Several natural molecules such as δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin, and phyllaemblicin B strongly binds to main protease | These molecules also showed strong binding with other potential targets of SARS-CoV-2 infection such as viral receptor human angiotensin-converting enzyme 2 (hACE2) and RNA-dependent RNA polymerase (RdRp) |
| Junior et al. [164] | 2021 | In silico | Docking and molecular dynamic (MD) simulation | Lapachol(1,4-naphthoquinone) | SARS-CoV-2 nonstructural proteins (nsps) | Lapachol derivatives VI and IX demonstrated the strongest binding | Lapachol derivatives are potential ligands for SARS-CoV-2 Nsp9 |
| Kar et al. [165] | 2020 | In silico | Molecular docking molecular dynamic simulations and analysis of MM-PBSA energy | Indian plants including Justicia adhatoda, Ocimum sanctum, and Swertia chirata | Spike protein, main protease enzyme Mpro, and RNA-dependent RNA polymerase (RdRp) | Anisotine against SARS-CoV-2 spike and Mpro proteins and amarogentin against RdRp as potential inhibitors | |
| Khalifa et al. [166] | 2020 | In silico | Molecular docking modeling structural-relationship activity | 10 anthocyanins | Main protease | Phacelianin, gentiodelphin, cyanodelphin, tecophilin | Leading molecules for further optimization and drug development process to combat COVID-19 |
| Khalifa et al. [167] | 2020 | In silico | Molecular operating environment molecular docking | 19 structural different hydrolysable tannins | Main protease | Pedunculagin, tercatain, and castalin | |
| Khan et al. [168] | 2020 | In silico | Molecular docking | Marine natural products | Main protease | C-1 (PubChem CID 11170714) exhibited good activity | |
| Kiran Raj et al. [169] | 2020 | In silico | Molecular docking | C-Phycocyanin of Spirulina platensis | Nonstructural proteins 12 | C-Phycocyanin inhibits the active site of nsp12 | |
| Krupanidhi et al. [170] | 2020 | In silico | Molecular docking molecular dynamic simulation ADME along with toxicity analysis | Phytochemical constituents of Tinospora cordifolia | Main protease | Tinosponone | |
| Kumar et al. [171] | 2020 | In silico | Molecular docking molecular dynamic simulations and analysis of MM-PBSA energy | Novel natural metabolites | Main protease | Ursolic acid, carvacrol, and oleanolic acid could | |
| Kumar et al. [172] | 2021 | In silico | Molecular docking, ADMET, and molecular dynamic simulations | Phytoconstituents from natural herbs | Main protease | Laurolitsine | Laurolitsine, an active constituent of roots of Lindera aggregata |
| Kumar et al. [173] | 2021 | In silico | Molecular docking molecular dynamic simulations and analysis of MM-PBSA energy | Strychnos nux-vomica | Main protease | Demethoxyguiaflavine, strychnoflavine | |
| Li et al. [174] | 2021 | In silico | Network pharmacology and in vitro experiment verification molecular docking | Maxing Shigan decoction (MXSGD) | ACE2, Mpro, and RdRp | The components with strong potential affinity (top 10) with ACE2, Mpro, and RdRp are mainly from Glycyrrhiza uralensis (Chinese name: Gancao) and Semen armeniacae amarum (Chinese name: Kuxingren). Among them, amygdalin was selected as the optimal candidate component binds to all three key targets, and euchrenone, glycyrrhizin, and glycyrol also exhibited superior affinity interactions with ACE2, Mpro, and RdRp, respectively | Multicomponent, multitarget, and multi-approach intervention |
| Maiti and Banerjee [175] | 2021 | In silico | Bioinformatic molecular docking | Tea flavonoid catechin products | Spike glycoproteins | Epigallocatechin gallate and theaflavin gallate interact better than hydroxychloroquine | |
| Mahmud et al. [176] | 2021 | In silico | Molecular docking molecular dynamic simulation MM-GBSA scores | 3063 compounds from more than 200 plants from the Asian region | Main protease | Curcumin, gartanin, robinetin | |
| Mahmud et al. [177] | 2020 | In silico | Molecular docking molecular dynamic simulation MM-GBSA scores | Plant-derived natural compounds | Main protease | Carinol, albanin, myricetin | |
| Mesli et al. [178] | 2021 | In silico | Molecular docking molecular dynamic simulations | Leaves of Corchorus olitorius Linn. | Angiotensin-converting enzyme 2 | Méthyl-1,4,5-tri-O-caféoyl quinate has a stronger bond, high affinity, and gives the best docking scores compared with the co-crystallized inhibitor (PRD_002214) of the enzyme ACE2 | |
| Mohammadi et al. [179] | 2020 | In silico | Molecular docking | Marine polypeptides were isolated from the hydrolysate of Pacific oyster | Main protease | The score of Leu-Leu-Glu-Tyr-Ser-Ileu ligand was higher than remdesivir | Pacific oyster compounds may have the potency to be evolved as an anti-COVID-19 main protease |
| Murugan et al. [180] | 2020 | In silico | Molecular docking molecular dynamic simulation MM-GBSA scores | Andrographis paniculata phytochemicals | 3 nonstructural proteins (3 L main protease (3CLpro), papain-like proteinase (PLpro) and RNA-directed RNA polymerase (RdRp)), and a structural protein (spike protein (S)) | Neoandrographolide (AGP3) has shown promising binding affinity towards all the four targets | |
| Naik et al. [181] | 2020 | In silico | Molecular docking molecular dynamic simulation ADME properties | Natural product activity and species source (NPASS) database | Endoribonuclease exoribonuclease RNA-dependent RNA polymerase (RdRp) methyltransferase and main protease | 21 compounds showed maximum docking scores NPC214620, NPC52382, and NPC270578 are targeting five, four, and three-drug targets, respectively | Multitarget-based drug design |
| Narkhede et al. [182] | 2020 | In silico | Molecular docking molecular dynamic simulations | Natural products | Main protease | Glycyrrhizin, bicyclogermacrene, tryptanthrin, β-sitosterol, indirubin, indican, indigo, hesperetin, chrysophanic acid, rhein, berberine, and β-caryophyllene | Interactions with the COVID-19 main protease were highest in the case of glycyrrhizin and rhein |
| Nivetha et al. [183] | 2020 | In silico | Molecular docking molecular dynamic simulation MM-PBSA | Seselin purified from the leaf extracts of Aegle marmelos | Spike protein S2, main protease, and free enzyme of the SARS-CoV-2 | Seselin had inhibitory potential over multiple SARS-CoV-2 targets | |
| Ogunyemi et al. [184] | 2020 | In silico | Molecular docking molecular dynamic simulation ADME properties | 226 bioactive compounds from African herbs and medicinal plants | RNA-dependent RNA polymerase | Drugable alkaloids (10′-hydroxyusambarensine, cryptospirolepine, strychnopentamine) and flavonoids (usararotenoid A and 12α-epi-millettosin) | |
| Padhi et al. [185] | 2021 | In silico | Molecular docking ADME properties | 415 natural metabolites isolated from several plants, fungi, and bacteria | Spike glycoprotein (S1) and the main protease | Fusaric acid, jasmonic acid, jasmonic acid methyl ester, putaminoxin, putaminoxins B and D, and stagonolide K were predicted to have considerable (ADME) and safety indices | Jasmonic acid and putaminoxins B and D bind best to main protease |
| Pandey et al. [186] | 2020 | In silico | Molecular docking molecular dynamic simulation ADME properties | 10 potential naturally occurring compounds (flavonoids/non-flavonoids) | Spike glycoprotein | Fisetin, quercetin, and kaempferol consist of drug-likeness property | |
| Kumar et al. [187] | 2020 | In silico | Molecular docking | Kabasura kudineer and thonthasura kudineer are two Siddha formulations | Spike glycoprotein | Cucurbitacin B (−112.09), cardiofolioside (−111.5), apigenin (−98.84), and pyrethrin (−92.98) were observed as more effective with less bind energies | Kabasura kudineer could be a potential Siddha medicine for COVID-19 |
| Rahman et al. [188] | 2021 | In silico | Molecular docking ADMET properties | Rutin | Main protease (Mpro), RNA-dependent RNA polymerase (RdRp), papain-like protease (PLpro), and spike (S) protein | Significant binding of rutin with Mpro, RdRp, PLpro, and S proteins. Main protease exhibited the strongest binding affinity | Optimal solubility, nontoxic, and noncarcinogenic properties |
| Rahman et al. [189] | 2020 | In silico | Molecular operating environment (MOE) ligand-based pharmacophore approach and a molecular docking-based screening | Natural product activity and species source (NPASS) | Type II transmembrane serine protease (TMPRSS2) | 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2 | |
| Rakib et al. [190] | 2020 | In silico | Molecular docking | Bioactive phytocompounds isolated from Tinospora crispa | Main protease | The top nine hits might serve as potential anti-SARS-CoV-2 lead molecules, with three of them exerting biological activity | |
| Ramadhan et al. [191] | 2020 | In silico | Molecular docking | Etlingera elatior plant | Main protease | Ergosterol peroxide sitostenone | |
| Rangsinth et al. [192] | 2021 | In silico | Molecular docking ADMET properties | Natural products isolated from edible and medicinal mushrooms | Main protease | 6 of 25 compounds are the best drug-like property candidates, including colossolactone VIII, colossolactone E, colossolactone G, ergosterol, heliantriol F, and velutin | |
| Rivero-Segura et al. [193] | 2021 | In silico | Molecular docking molecular dynamic simulation ADME properties | Mexican natural products | Against the SARS-CoV-2 | Quercetin, riolozatrione, and cichoriin target the key proteins of SARS-CoV-2 | Cichoriin reaches higher lung levels (100 mg/kg, IV); therefore, it may be considered in developing therapeutic tools |
| Selvaraj et al. [194] | 2020 | In silico | Homology modeling and molecular dynamic (MD) simulation MM/GBSA, MD simulations, and PCA calculations | Traditional Chinese medicine (TCM) database | Nsp 14 guanine-N7 methyltransferase (N7-MTase) | TCM 57025, TCM 3495, TCM 5376, TCM 20111, and TCM 31007 are the compounds from the TCM database, which can occupy and interact nicely with the substrate-binding site of N7-MTase | |
| Sharma and Kaur [195] | 2021 | In silico | Molecular docking, protein interaction calculator ADME studies | 12 bioactive molecules present in essential oils of eucalyptus plant leaves | Spike (S) protein | Toruatone | |
| Sharma [196] | 2020 | In silico | Molecular docking, protein interaction calculator | Eucalyptol (1,8 cineole), an essential oil component from eucalyptus oil | Main protease | Eucalyptol may represent potential treatment potential to act as main protease inhibitor | Effective binding of eucalyptol to COVID-19 proteinase |
| Sharma and Kaur [197] | 2020 | In silico | Molecular docking, protein interaction calculator | Jensenone, an essential oil component from eucalyptus oil | Main protease | Jensenone may represent potential treatment potential to act as main protease inhibitor | |
| Shawan et al. [198] | 2021 | In silico | Pharmacophore study molecular docking molecular dynamic simulation ADME properties | 43 flavonoids of 7 different classes | Against the SARS-CoV-2 | Luteolin and abyssinone II were found to develop successfully docked complex within the binding sites of target proteins | |
| Sindhu et al. [199] | 2020 | In silico | Molecular docking | Clerodendrum paniculatum leaves | Main protease | Clerodol | |
| Singh et al. [200] | 2021 | In silico | Molecular docking and structural dynamic studies | Tea (Camellia sinensis) polyphenols | Nonstructural protein 16 (NSP16) | Theaflavin compound demonstrated lower binding free energy in comparison with the standard molecule sinefungin | |
| Singh et al. [201] | 2020 | In silico | Molecular docking and structural dynamic studies molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) ADME properties | Polyphenols | RNA‐dependent RNA polymerase (RdRp) | EGCG, theaflavin (TF1), theaflavin-3′-O-gallate (TF2a), theaflavin-3′-gallate (TF2b), theaflavin 3,3′-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp | EGCG, TF2a, TF2b, and TF3 can inhibit RdRp and represent an effective therapy for COVID-19 |
| Srimathi et al. [202] | 2020 | In silico | Molecular docking | Traditional herbal medicine: apo-quinine, catechin, cinchonidine, cinchonine, cupreidine, epicatechin, epiprocurcumenol, epiquinine, procurcumenol, quinidine, quinine, zedoaronediol, procurcumadiol | Against the SARS-CoV-2 | Epicatechin, apo-quine | |
| Subbaiyan et al. [203] | 2020 | In silico | Molecular docking | Active constituents present in common herbs | Spike (S) protein | Epigallocatechin gallate (EGCG) was found to have the highest binding affinity with the viral S protein, followed by compounds, “F” (curcumin), “D” (apigenin), and “E” (chrysophanol) | Green tea |
| Surti et al. [204] | 2020 | In silico | Molecular docking molecular dynamic simulations | Ilimaquinone (marine sponge metabolite) | Spike receptor-binding domain, RNA-dependent RNA polymerase, Nsp10, Nsp13, Nsp14, Nsp15, Nsp16, main protease, and papain-like protease | Ilimaquinone exhibited promising inhibitory potential against all the SARS-CoV-2 target proteins, as evident from the binding energies | Most promising inhibitory candidate against the SARS-CoV-2 papain-like protease |
| Tao et al. [205] | 2020 | In silico | Network pharmacology and molecular docking. | Huashi Baidu formula (HSBDF): Chinese | Against the SARS-CoV-2 | Baicalein and quercetin were the top two compounds of HSBDF, which had high affinity with ACE2 | Regulate multiple signaling pathways through ACE2 |
| Umar et al. [206] | 2021 | In silico | Molecular docking molecular dynamic simulation ADME properties | Azadirachta indica, Mangifera indica, and Moringa oleifera: African plants | Main protease | Most of the active phytocomponents of the study plants exhibited relative inhibitory potentials against main protease and preferred pharmacological features when compared with hydroxychloroquine | Caffeic acid, chlorogenic acid, catechin, ellagic acid, gallic acid, etc. |
| Umesh et al. [207] | 2021 | In silico | Molecular docking molecular dynamic simulation ADME properties | Chemical compounds from Indian spices | Main protease | Carnosol exhibited the highest binding affinity for arjunglucoside-I and rosmanol showed a strong and stable binding affinity with favorable ADME properties | |
| Yang et al. [208] | In silico | 2020 | High-throughput virtual screening | Natural Products Research Laboratories (NPRL) | Main protease | Curcuminoid derivatives (including NPRL334, NPRL339, NPRL342, NPRL346, NPRL407, NPRL415, NPRL420, NPRL472, and NPRL473) display strong binding affinity to COVID-19 3Lpro polyprotein | NPRL-334 revealed the strongest binding affinity |
| Yu et al. [209] | 2020 | In silico | Metascape analysis protein docking molecular docking | Mongolian medicine | SARS-CoV-2 S protein RBD domain | 253 active components were predicted. Phillyrin and chlorogenic acid can effectively prevent the combination of SARS-CoV-2 S protein and ACE2 at the molecular level | |
| Zhang et al. [210] | 2020 | In silico | Molecular docking molecular dynamic simulation ADME property network pharmacology analysis | Chinese herbal medicines | Anti-2019-nCoV activity | 13 compounds that exist in traditional Chinese medicines were found to have potential anti-2019-nCoV activity. 125 Chinese herbs were found to contain 2 or more of these 13 compounds. Of these 125 herbs, 26 are classically cataloged as treating viral respiratory infections | Regulating viral infection, immune/inflammation reactions, and hypoxia response |