Table 2.
Molecular docking outcomes of in silico studies modeling the interaction of propolis constituents with SARS-CoV-2.
| Study | Comparator: binding affinity energy (kcal/mol) | Study compound (binding affinity energy [kcal/mol]) | Summary |
|---|---|---|---|
| Angiotensin-converting enzyme 2 | |||
| Guler et al. [7] | MLN-4760: −7.24 | Caffeic acid (−5.53), caffeic acid phenethyl ester (−7.58), chrysin (−7.17), galangin (−7.35), myricetin (−7.59), rutin (−8.04), hesperetin (−7.45), pinocembrin (−7.16), luteolin (−7.29), quercetin (−7.58), kaempferol (−7.23), and syringic acid (−4.49) | Rutin had the highest binding affinity compared to the other 11 compounds, which was higher than the reference compound MLN-4760 |
| Khayrani et al. [8] | MLN-4760: −9.2 | Sulabiroins A (−9.5), sulabiroins B (−8.8), 2,3-dihydro-3-hydroxypapuanic acid (−8.3), (−)-papuanic acid (−8.5), (−)-isocalolongic acid (−8.9), isopapuanic acid (−8.1), isocalopolyanic acid (−8.8), glyasperin A (−10.8), broussoflavonol F (−9.9), (2S)-5,7-dihydroxy-40-methoxy-8-prenylflavanone (−9.3), isorhamnetin (−9.2), (1S)-2-trans, 4-trans-abscisic acid (−7.3), and (1S)-2-cis, 4-trans-abscisic acid (−7.2) | Glyasperin A had the highest binding affinity compared to the other 12 compounds, which was higher than MLN-4760 |
| Main protease | |||
| Dewi et al. [26] | Native ligand (N3): −8.4 | Sulabiroins A (−8.1), sulabiroins B (−7.8), 2′,3′-dihydro-3′-hydroxypapuanic acid (−7.1), (−)-papuanic acid (−7.4), (−)-isocalolongic acid (−7.2), isopapuanic acid (−7.0), isocalopolyanic acid (−6.4), glyasperin A (−7.8), broussoflavonol F (−7.9), (2S)-5,7-dihydroxy-4′-methoxy-8-prenylflavanone (−7.9), isorhamnetinb (−7.3), (1′S)-2-trans,4-trans-abscisic acid (−6.5), (1′S)-2-cis,4-trans-abscisic acid (−6.0), curcumene (−5.5), thymol (−4.7), tetralin (−4.7), P-coumaric acid (−5.1), α-tocopherol succinate (−6.2), deoksi podophyllotoxin (−7.4), and xanthoxyletin (−6.7) | Sulabiroins A had the highest binding affinity compared to the other 19 compounds, which was lower than native ligand (N3) |
| Elwakil et al. [16] | Lopinavir: −8.18 | Acid: n-hexadecanoic acid (−6.28), benzoic acid (−3.70), trans-caffeic acid (−4.48), tetradecanoic acid (−5.84), and trans-13-octadecenoic acid (−6.06) | Octacosanol showed the highest binding affinity compared to the other 25 compounds, which was lower than lopinavir |
| Alkanes: heneicosane (−6.44), octacosane (−7.39), and heptacosane (−6.95) | |||
| Esters: hexadecanoic acid, methyl ester (−6.28), pinostrobin chalcone (−5.44), hexadecaneperoxoic acid, 1,1-dimethyl-3-[(1-oxohexadecyl)oxy]propyl ester (−7.35), oxalic acid, dodecyl 2-phenylethyl ester (−6.94), and methyl pentafluoropropionate (−3.40) | |||
| Triterpenoids: R1-barrigenol (−5.81), α-eudesmol (−4.61), and ß-eudesmol (−4.77) | |||
| Alcohol: octacosanol (−6.77) | |||
| Flavoniods: pinocembrin (−5.29) | |||
| Unspecified: bicyclo[2.2.2]octa-2,5-diene, 1,2,3,6-tetramethyl (−4.23), estra-1,3,5(10)-trien-17-one, 3-hydroxy-2-methoxy (−6.16), pregnan-20-one, 3,17-dihydroxy-,(3ß,5ß) (−5.53), octadecane, 3-ethyl-5-(2-ethylbutyl) (−6.55), 4ß-methylandrostane 2,3-diol-1,17-dione (−5.38), octatriacontyl pentafluoropropionate (−7.35), pregn-5-en-20-one, 11-(acetyloxy)-3,14-dihydroxy-12-(2-hydroxy-3-methyl-1-oxobutoxy)-,(3ß,11α,12ß,14ß) (−6.08), and cyclohexamine, N-n-butyl-1-[2-thionaphthenyl] (−5.33) | |||
| Harisna et al. [25] | Nelfinavir: −7.7 | Flavones: 3′-methoxydaidzein (−7.3), 3′-methoxydaidzin (−7.7), genistin (−7.6), xanthomicrol (−7.1), 3′,5,6,7-tetrahydroxy-4′-methoxyisofavone (−7.6), methylophiopogonone A (−7.6), 3′4′,7-trihydroxyfavanone (−7.5), moslosoofavone (−7.4), luteolin (−7.5), 2′,6′-dihydroxy-4′ methoxydihydrochalcone (−6.9), chrysoeriol (−7.3), jaceosidin (−7.2), (3R)-7,2′,3′-trihydroxy-4′-methoxyisofavanone (−7.1), and neobavaisofavone (−7.6) | 3′-Methoxydaidzin showed the highest binding affinity compared to the other 21 compounds but was similar to nelfinavir for the SARS-CoV-2 main protease |
| Flavonols: 3′-deoxysappanol (−7.0) | |||
| Phenolic acid: cinnamic acid (−5.4), caffeic acid (−5.9), 2,5-dimethyl-7-hydroxychromone (−6.2), isoferulic acid (−5.7), dimethylcaffeic acid (−5.7), benzyl caffeate (−7.1), and isoaloeresin D (−7.4) | |||
| Refaat et al. [27] | Native ligand (N3): −133.6; remdesivir: −136.4; favipiravir: −33.3; hydroxychloroquine: −65.9 | Rutin (−92.8), caffeic acid phenethyl ester (−67.8), quercetin (−57.5), kaempferol (−56.3), pinocembrin (−56.2), pinobanksin (−54.1), galangin (−53.2), chrysin (−52.9), p-cumaric acid (−45.5), and benzoic acid (−35.4) | Rutin had the highest binding affinity compared to the other 9 compounds, which was higher than favipiravir and hydroxychloroquine. However, it was lower than native ligand (N3) and remdesivir for the SARS-CoV-2 main protease |
| Sahlan et al. [28] | 13b: −8.2 | New podophyllotoxin derivative: sulabiroins A (−7.6) | Glyasperin A and broussoflavonol F had the highest binding affinity compared to the other 19 compounds, but they were lower than 13b for the SARS-CoV-2 main protease |
| Others: sulabiroins B (−7.0), 2′,3′-dihydro-3′-hydroxypapuanic acid (−6.7), (−)-papuanic acid (−6.6), (−)-isocalolongic acid (−6.7), isopapuanic acid (−6.8), isocalopolyanic acid (−6.8), glyasperin A (−7.8), broussoflavonol F (−7.8), (2s)-5,7-dihydroxy-4′-methoxy-8-prenylflavanone (−7.1), isorhamnetin (−7.5), (1′s)-2-trans,4 trans-abscisic acid (−6.1), (1′s)-2-cis,4 trans-abscisic acid (−5.9), a-tocopherol succinate (−5.1), xanthoxyletin (−6.2), P-coumaric acid (−4.9), curcumene (−4.7), thymol (−4.7), tetralin (−4.4), deoxypodophyllotoxin (−7.3), and 14b (−7.2) | |||
| Shaldam et al. [29] | Not available | 2,2-Dimethyl-8-prenylchromene (−6.8) | Kaempferol had the highest binding affinity compared to 13 other compounds |
| Phenylpropanes: artepillin C (−7.5), 3-prenyl cinnamic acid allyl ester (−6.2), isocupressic acid (−6.4), 13C-symphyoreticulic acid (−6.9), ellagic acid (−7.5), syringic acid (−5.6), caffeic acid phenethyl ester (−7.0), p-coumaric acid (−5.6), hesperetin (−7.4), naringenin (−6.5), kaempferol (−7.8), quercetin (−7.4), and chrysin (−7.2) | |||
| RNA-dependent RNA polymerase | |||
| Elwakil et al. [16] | Remdesivir: −6.77 | Acid: n-hexadecanoic acid (−5.70), benzoic acid (−3.91), trans-caffeic acid (−4.80), tetradecanoic acid (−5.34), and trans-13-octadecenoic acid (−5.97) | Octatriacontyl pentafluoropropionate had the highest binding affinity compared to the other 24 compounds, which was higher than the reference drug, remdesivir |
| Alkanes: heneicosane (−6.19), octacosane (−6.87), and heptacosane (−6.91) | |||
| Esters: hexadecanoic acid, methyl ester (−5.63), pinostrobin chalcone (−5.59), hexadecaneperoxoic acid, 1,1-dimethyl-3-[(1-oxohexadecyl)oxy]propyl ester (−8.04), oxalic acid, dodecyl 2-phenylethyl ester (−6.94), and methyl pentafluoropropionate (−3.54) | |||
| Triterpenoids: R1-barrigenol (−5.58), α-eudesmol (−4.47), and ß-eudesmol (−4.96) | |||
| Alcohol: octacosanol (−6.96) | |||
| Flavoniods: pinocembrin (−4.93) | |||
| Not specified: Bicyclo[2.2.2]octa-2,5-diene, 1,2,3,6-tetramethyl (−3.84), estra-1,3,5(10)-trien-17-one, 3-hydroxy-2-methoxy (−5.31), pregnan-20-one, 3,17-dihydroxy-, (3ß,5ß) (−5.06), octadecane, 3-ethyl-5-(2-ethylbutyl) (−6.11), 4ß-methylandrostane 2,3-diol-1,17-dione (−4.72), octatriacontyl pentafluoropropionate (−8.20), pregn-5-en-20-one,11-(acetyloxy)-3,14-dihydroxy-12-(2-hydroxy-3-methyl-1-oxobutoxy)-(3ß,11α,12ß,14ß) (−6.63), and cyclohexamine, N-n-butyl-1-[2-thionaphthenyl] (−4.90) | |||
| Shaldam et al. [29] | Not available | 2,2-Dimethyl-8-prenylchromene (−5.6) | Ellagic acid had the highest binding affinity compared to the other 13 compounds |
| Phenylpropanes: artepillin C (−5.9), 3-prenyl cinnamic acid allyl ester (−5.3), isocupressic acid (−5.8), 13C-symphyoreticulic acid (−5.7), ellagic acid (−6.4), syringic acid (−5.5), caffeic acid phenethyl ester (−5.4), p-coumaric acid (−5.3), hesperetin (−6.3), naringenin (−6.0), kaempferol (−6.2), quercetin (−6.1), and chrysin (−6.1) | |||
| Spike protein subunit 1 | |||
| Elwakil et al. [16] | Umifenovir: −5.56 | Acid: n-hexadecanoic acid (−5.64), benzoic acid (−4.16), trans-caffeic acid (−4.76), tetradecanoic acid (−5.23), and trans-13-octadecenoic acid (−5.29) | Octatriacontyl pentafluoropropionate showed the highest binding affinity, compared to the 25 other compounds, which was higher than umifenovir |
| Alkanes: heneicosane (−5.68), octacosane (−5.99), and heptacosane (−5.80) | |||
| Esters: hexadecanoic acid, methyl ester (−5.27), pinostrobin chalcone (−5.50), hexadecaneperoxoic acid,1,1-dimethyl-3-[(1-oxohexadecyl)oxy]propyl ester (−6.56), oxalic acid, dodecyl 2-phenylethyl ester (−5.95), and methyl pentafluoropropionate (−3.55) | |||
| Triterpenoids: R1-barrigenol (−4.44), α-eudesmol (−4.57), and ß-eudesmol (−4.96) | |||
| Alcohol: octacosanol (−6.26) | |||
| Flavoniod: pinocembrin (−4.78) | |||
| Not specified: bicyclo[2.2.2]octa-2,5-diene, 1,2,3,6-tetramethyl (−3.93), estra-1,3,5(10)-trien-17-one, 3-hydroxy-2-methoxy (−5.26), pregnan-20-one, 3,17-dihydroxy-, (3ß,5ß) (−4.36), octadecane, 3-ethyl-5-(2-ethylbutyl) (−5.83), 4ß-methylandrostane 2,3-diol-1,17-dione (−4.64), octatriacontyl pentafluoropropionate (−6.96), pregn-5-en-20-one, 11-(acetyloxy)-3,14-dihydroxy-12-(2-hydroxy-3-methyl-1-oxobutoxy)-,(3ß,11α,12ß,14ß) (−5.03), and cyclohexamine, N-n-butyl-1-[2-thionaphthenyl] (−5.5) | |||
| Jain et al. [30] | Dexamethasone: −7.9 | Flavonoids: chrysin (−8.1), and galangin (−8.2) | Chrysin and galangin showed higher binding affinity than dexamethasone |
| Refaat et al. [27] | Remdesivir: −165.9; faviripavir: −46.3; hydroxychloroquine: −79.8 | Rutin (−94.3), caffeic acid phenethyl ester (−77.8), quercetin (−67.8), kaempferol (−62.3), pinocembrin (−60.5), pinobanksin (−77.4), galangin (−59.5), chrysin (−66.2), p-cumaric acid (−56.5), and benzoic acid (−40.4) | Rutin had the highest binding affinity compared to the other 9 compounds which was higher than favipiravir and hydroxychloroquine but lower than remdesivir |
| Spike protein subunit 2 | |||
| Harisna et al. [25] | Pravastatin: −7.3 | Flavones: 3′-methoxydaidzein (−7.6), 3′-methoxydaidzin (−8.3), genistin (−8.3), xanthomicrol (−7.0), 3′,5,6,7-tetrahydroxy-4′-methoxyisofavone (−7.8), methylophiopogonone A (−8.2), 3′4′,7-trihydroxyfavanone (−7.6), moslosoofavone (−7.4), luteolin (−7.7), 2′,6′-dihydroxy-4′ methoxydihydrochalcone (−6.7), chrysoeriol (−7.7), jaceosidin (−7.3), (3R)-7,2′,3′-trihydroxy-4′-methoxyisofavanone (−7.5), and neobavaisofavone (−8.1) | 3′-Methoxydaidzin and genistin had the highest binding affinity compared to the other 20 compounds, which was higher than pravastatin |
| Flavonols: 3′-deoxysappanol (−7.0) | |||
| Phenolic acid: cinnamic acid (−5.3), caffeic acid (−5.5), 2,5-dimethyl-7-hydroxychromone (−6.1), isoferulic acid (−5.6), dimethylcaffeic acid (−5.7), benzyl caffeate (−6.5), and isoaloeresin D (−7.8) | |||
MLN-4760: (S,S)-2-{1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino}-4-methylpentanoic acid; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.