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 phytocompounds | References |
| Tannins | Punicalin (3-IR and −7.406 BE), punicalagin (6-IR and −7.312 BE), Pedunculagin (4-HB, 6 NBI and −7.7 BE), punigluconin (7-HB, 5-NBI and −7.9 BE), chebulagic acid (5-HB, 5-NBI and −7.5 BE), chebulinic acid (5-HB, 7-NBI and −6.5 BE), cinnamtannin-B1 (3-HB, 3-HP and −10.2 BE), 6-Glucopyranosyl procyanidin-B1 (8-HB, 1-EI and −9.9 BE), Procyanidin-B7 (2-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), gallic acid (2 IR and −4.808 BE), gallotannins (6 HB, 7-NBI, −7.4 BE). | Phe40, Leu95, Gln102, Asn103, Lys187, Asp206, Val209, Asn210, Leu335, Phe342, Asn343, Pro346, Thr347, Trp349, Val367, Leu368, Tyr369, Asn370, Ser371, Ala372, Phe374, Phe377, Asp382, Phe390, Arg393, Asn394, Glu398, Gln493, Ala396, His401, Glu402, Arg403, Glu406, Gln409, Lys417, Tyr449, Tyr453, Leu455, Phe456, Tyr489, Phe490, Leu492, Gln493, Ser494, Tyr495, Gln496, Asn501, Tyr505, Asp509, Arg514, Tyr515, Lys562, Lys562, Pro565 | [56,66,79]. |
| Terpenoids | Geraniol (2-HB and-5.0 BE), L-4-terpineol (2-HB and −5.1 BE), carvacrol (1-HB and −5.2 BE), limonene (12-HPI and −5.1 BE), thymol (-5.4 BE), tinosporide (2HB, 6-NBI and −6.4 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 (−4.8 BE), α-terpinene (−5.0 BE), camphene (2-HPI and −5.2 BE), camphor (2-HPI and −4.8 BE). | Leu73, Asp350, Tyr385, Phe390, Asn394, Arg403, Asp405, Glu406, Arg408, Gln409, Gly416, Lys417, Tyr449, Tyr451, Leu452, Tyr453, Leu455, Phe-456, Lys458, Ser-459, Leu461, Ile468, Thr470, Ile472, Glu484, Tyr489, Phe490, Pro491, Leu492, Gln493, Ser494, Tyr495, Gly496, Asn501, Tyr505 | [47,56,66] |
| Flavonoids | 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-l-arabinofuranoside 7-rhamnoside (7-HB, 2-HP and −8.7 BE), catechin gallate (5 HB, 3 HP and −6.1 BE), cinnamaldehyde (2-HB and −5.0 BE), Anthranol (1 HB, 2 HP and-9.08 BE),Apigenin (5 HB, 2 HP and -10.09 BE)Derrisin (2 HB, 2 HP and -11.04 BE)Jaceidin (2 HB, 2 HP and -10.54 BE),Lupiwighteone (1 HB, 3 HP and -9.92 BE), Luteolin (2 HB, 2 HP and -10.92 BE), Mundulinol (2 HB, 1 HP and -11.08 BE), Naringenin (2 HB, 2 HP and -10.12 BE), Rhamnetin (2 HB, 2 HP and -10.15 BE), Tamarixetin (2 HB, 1 HP and -10.33 BE), Cannflavin (1 HB, 2 HP and -9.11 BE), Methylglovanon (1 HB, 1 HP and -9.43 BE) | Ser44, Leu48, Ala292,Cys301, Leu303, Ile312, Tyr313, Thr315, Asn317, Phe318, Arg319, His345, Thr347, Ala348, Trp349, Asp350, His374, Glu375, His378, Asp382, Tyr385, Gly395, Asn397, Glu398, His401, Arg403, Glu406, Tyr410, Lys417, Arg443, Ser448, Asn449, Tyr453, Arg454, Leu455, Phe456, Ser459, Glu471, Val472, Glu473, Gly474, Phe475, Phe486, Tyr484, Thr487, Asn488, Ser494, Tyr495, Gly496, Phe497, Tyr505, Tyr510, Arg514, Tyr515, Gln516, Leu517, His519, Ala520, Ala522, Asn544, Gly545, Leu546, Val595, Pro665, Ser730, Met731, Lys733, Gln762, Arg765, Ala766, Asn856, Val860, Pro863, Asp867, Asp867, Lys964, Leu966, Ser967, Phe970, Asn969, His1058. | [12,47,56,57,[25], [66]] |
| Steroids | Withametelin (8 NBI and −8.0 BE), withanolide-A (1-HB, 7-NBI and −7.7 BE), echinacin (2-HB, 6-NBI and −7.9 BE), stigmasterol (2-IR and −7.2 BE), withanolide G (4 HB, 2 HP and −8.4 BE) | Asp66, Arg67, Gln85, Val367, Asn370, Phe374, Tyr449, Leu452, Leu455, Phe456, Glu484, Tyr489, Phe490, Leu492, Gln493, Ser494. | [41,56,57] |
| Quinone | Emodin (4 IR and −6.19), rhein (5 IR and −8.73) | Asn332, Thr333, Asn353, Ser388, Val401, Asn448, Ala464, Val472, Gly474, | [12] |
| Steroidal saponins | Asparoside-C (5 HB and −7.54 BE), asparoside-D (6 HB and −7.06 BE), shatavarin-I (Asparoside-B) (5 HB and −6.52 BE), shatavarin-X (6 HB and −6.43 BE), racemoside-A (3 HB and −6.23) | Arg403, Glu406, Gln409, Gln414, Thr415, Lys417, Asp420, Lys444, Gly447, Tyr449, Tyr453, Glu484, Ser494, Gly496, Gly496, Gln498, Gly502 | [16] |
| Alkaloid | Chelidimerine (2 HB, 3 HP and −8.2 BE), Withanone (1 HB, 5 HP and −7.8 BE), Norsanguinarine (3 HB, 3 HP and −7.0 BE), Sanguinarine (1 HB, 4 HP and −6.8 BE), Adlumidine (3 HB, 4 HP and −6.8 BE), Somniferine (2 HB, 4 HP and −6.7 BE), Fumariline (1 HB, 3 HP and −6.4 BE) | Asp66, Arg67, Leu335, Phe338, Gly339, Phe342, Asn343, Asp364, Val367, Leu368, Leu368, Asn370, Ser371, Phe374, Trp436 | [57] |
| Sesquiterpene | Badrakemin acetate (3 HB, 5 HP, and −8.0 BE), Samarcandin (2 HB, 3 HP, and −7.4 BE) | Leu335, Phe338, Gly339, Glu340, Asn343, Asp364, Val367, Leu368 | [57] |
| 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 and −7.4 BE), deoxytubulosine (1-HB, 8-NBI and −7.2 BE) | Arg403, Asp405, Glu406, Gln409, Lys417, Tyr449, Tyr453, Arg454, Leu455, Phe456, Ser469, Glu471, Glu484, Gly485, Tyr489, Phe490, Leu492, Gln493, Ser494, Gly496, Asn501, Tyr505 | [47,56] |
| Standards |
Remidesvir (3 IR and −5.94 BE), chloroquine (3 IR and −8.98), hydroxychloroquine (4 IR and −7.82 BE) |
Arg403, Glu406, Tyr453, Thr467, Pro468, Cys469, Gly471, Val472 |
[12,16,41] [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 −12.76 BE), allyl (E)-1-propenyl disulfide (2 IR and −9.07 BE), allyl methyl trisulfide (2 IR and −12.50 BE), diallyl tetrasulfide (4 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). | Lys94, Gln98, Gln101, Gln102, Asn103, Gly205, Asp206, Glu208, Val209, Asn210, Ala396, Lys562, Ser563, Pro565, Trp566 | [82] |
| 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), punigluconin (5 HB, 5 HPI and −6.6 BE), chebulagic acid (1 HB, 6 HPI and −6.6 BE), chebulinic acid (4 HB, 3 HPI and −6.8 BE), gallotannins (4 HB, 7 HPI and −7.1 BE). | Asp30, Asn33, His34, Glu35, Glu37, Asp38, Tyr41, Ser280, Pro289, Asn290, Ile291, Asp292, Arg393, Lys353, Asp367, Ala386, Ala387, Gln388, Pro389, Arg393, Phe428, Lys441, Gln442, Thr445. | [79] |
| 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), quercetin (5 IR and −4.11 BE) | Thr27, Lys31, His34, Glu35, Glu37, Asp38, Gln42, Asn63, Thr125, Ile126, Thr129, Asn137, Pro138, Gly139, Lys353 | [[12], [100]] |
| 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 and −2.53 BE), p-thymol (3 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), beta-sitosterol (7 IR 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). | Lys26, Thr27, Asp30, Lys31, Asn33, His34, Glu35, Asp38, Glu37, Leu39, Phe40, Gln42, Asn90, Thr92, Val93, Gln96, Tyr127, Ser128, Glu145, Asn 149, Trp271, Arg273, Phe274, His345, Pro346, Thr347, Ala348, Trp349, Asp350, Lys353, Asp367, Lue370, Thr371, His373, His374, Glu375, Asp382, Tyr385, Ala387, Gln388, Pro389, Phe390, Arg393, Asn394, His401, Glu402, Glu406, Ser409, Gln442, Thr445, Leu503, Phe504, His505, Asn508, Arg514, Tyr515, Lys562 |
[[1], [87], [100]] |
| Alkaloids | Pellitorine (5 IR and −3.4 BE), vasicine (5 IR and −6.21 BE), piperidine (9 IR and −4.31 BE), piperine (5 IR and −4.1 BE) | Asp30, Lys31, Asn33, His34, Glu35, Glu37, Asp38, Phe40, Asp350, Lys353, Pro389, Phe390, Arg393, Asn394, | [100] |
| Standards |
Lopinavir (9 IR and −7.5 BE), umifenovir (7 IR and −6.5 BE), Hydroxychloroquine (10 IR and −7.1 BE) |
His34, Glu37, Thr276, Asn290, Ile291, Met366, Asp367, Leu370, Gln388, Pro389, Arg393, Lys403, Glu406, Ser409, Leu410, Ala413, Lys441, Thr445, Ser494, Tyr495, Gly496, Tyr505 |
[10,79] |
|
TMPRSS2 (host protease) | |||
| Class |
Small molecule inhibitors |
Interacting residues with different classes of phytocompounds |
References |
| Tannins | Punicalin (5 IR and −8.168 BE), punicalagin (6 IR and −7.358 BE), ellagic acid (2 IR and −6.829 BE), gallic acid (5 IR and −5.709 BE) | Arg87, Ala88, Arg91, Asp92, Asn97, Asp129, Tyr401, Met404, Arg405, Gly408 | [79] |
| Steroidal lactone | Withaferin-A (2 HB, 19 IR and −5.60 BE), Withanone (1 HB; 18 HP and −4.30 BE) | His296, Glu299, Tyr337, Lys342, Glu389, Asp435, Ser436, Cys437, Gln438, Asp440, Ser441, Thr459, Ser460, Trp461, Gly462, Ser463. Gly464, Cys465, Ala466, Gly472, Val473 | [49] |
| Caffeate ester | Caffeic acid phenethyl ester (2 HB; 17 HP and −6.20 BE) | Cys281, Val280, His296, Cys297, Glu299, Leu302, Asp435, Ser436, Cys437, Gln438, Gly439, Asp440, Ser441, Thr459, Ser460, Trp461, Gly462, Gly464, Cys465 | [49] |
| Standards |
Camostat (5 IR and −7.069 BE), Camostat mesylate (1 HB and 20 HPI and -5.9 BE) |
Arg87, Asn97, Phe99, Met404, Arg405, Val275, Gln276, Val278, Val 280, His296, Cys297, Leu302, Asp435, Ser436, Cys437, Gln438, Gly439, Ser441, Thr459, Trp461, Gly462, Cys465, Ala466, Gly472, Val473 |
[79] [49] |
|
Furin (host protein) | |||
| Class |
Small molecule inhibitors |
References |
|
| Tannins | Punicalin (7 IR and −9.725 BE), punicalagin (4 IR and −9.385 BE), ellagic acid (5 IR and −7.801 BE | His194, Gly255, Pro256, Pro256, Glu257, Asp258, Asp259, Thr262, Arg298, Cys303, Asp306, Gly307, Ser311, Gly366, Ser368, Thr365, Arg 490, Trp531, Ala532, | [79] |
| Standards |
Sulcanozole (4 IR and −6.923 BE) |
Val263, Phe528, Trp531, Ala532 |
[79] |
|
Papain-like protease/nsp3 (viral protease) | |||
| Class |
Small molecule inhibitors |
Interacting residues with different classes of phytocompounds |
References |
| Terpenoid, Flavonoid |
Oleonolic acid (4 IR and −10 BE), ursolic acid (5 IR and −9.7 BE), 3β-acetoxyolean-12-en-27-ioc acid (3 IR and −9.5 BE), Isovitexin (5 IR and −9.3 BE) |
His89, Trp106, Ala107, Asp108, Asn109, Val159, Gly160, Gu161, Leu162, Pro248, Tyr264 |
[55] |
| 3 Chymotrypsin-like protease/nsp5 (viral protease) | |||
| Class |
Small molecule inhibitors |
Interacting residues with different classes of phytocompounds |
References |
| Flavonoid |
Epigallocatechin (6 IR and −7.0 BE), gallocatechin (6 IR and −7.1 BE) catechin (6 IR and −7.1 BE), epicatechin (6 IR and −7.2 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-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 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-rutinoside 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). |
Lys5, Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Met49, Tyr53, Tyr54, Pro108, Lys137, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu-166, Leu-167, Pro168, His172, Asp187, Arg188, Gln189, Thr190, Ala191, Gln192, Gly195, Asp197, Thr199, Asn238, Tyr239, His246, Leu271, Leu272, Leu286, Leu287, Glu288, Asp289. | [[20], [57], [66], [67], [73], [109]] |
| Organosulfur | Allyl disulfide (6 IR and −15.32 BE), allyl trisulfide (4 IR and −15.02 BE), allyl (E)-1-propenyl disulfide (2 IR and −13.25 BE), 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) | Leu141, Asn142, Gly143, Ser144, Cys145, His163, Met165, Glu166 | [82] |
| Terpenoids | Glycyrrhizic acid (4 HB, 3 CHB, 12 VDW and −8.7 BE), 6-oxoisoiguesterin (5 IR and −9.1 BE), daturaolone (10 NBI and −7.3 BE), glycyrrhizin (7 HB; 7 NBI and −8.2 BE), calendulaglycoside B (16 IR and −8.2 BE), calenduloside (15 IR and −7.9), tenuifolin (6 HB, HP-2 and 8.8 BE), 7-Deacetyl-7-benzoylgedunin L (1 CHB, 2 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) | Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Met49 Leu50, Tyr118, Arg131, Lys137, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, Leu167, Pro168, His172, Asp187, Arg188, Gln189, Thr190, Ala191, Tyr239, Leu275, Leu286, Leu287 | [21,31,51,56,87] |
| Sesquiterpene | Badrakemin acetate (2 HB, 5 HP and −8.6 BE), Samarcandin (3 HB, 2 HP and −8.5 BE) | His41, Gly143, Cys145, His163, Glu166, Leu167, Pro168, Gln192 | [57] |
| 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 −6.04 BE); bisdemethoxycurcumin (5 IR and −7.3 BE) | His41, Asn119, Phe140, Cys145, His163 | [73] |
| 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, Gln189, Thr190 | [43] |
| 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); Delphinidin 3,3′-Di-Glucoside-5-(6-P-Coumarylglucoside) (28 IR and −11.59 BE), 2-(3,4,5-Trihydroxyphenyl)-3-[6-[(E)-3-(4-hydroxyphenyl) acryloyl]-beta-D-galactopyranosyloxy]-5,7-dihydroxy-1-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) |
Thr24, Thr25, Thr26, Leu27, His41, Cys44, Met49, Leu50, Pro52, Tyr54, Gly138, Ser139, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, Leu167, Pro168, Thr169, Gly170, His 172, Val186, Asp187, Arg188, Gln189, Thr190, Ala191, Gln192 | [27,57] |
| 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), Withanolide G (4 HB, 4 HP and −8.6 BE) | Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Met49, Leu50, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, Leu167, Pro168, Arg188, Gln189, Thr190, Ala191, Gln192 | [57,84] |
| Alkaloid | 10-Hydroxyusambarensine ( 10 IR and −10.1 BE), cryptoquindoline (3 IR and −9.7 BE); 6-Oxoisoiguesterin (1 HB, 4 IR and −9.1 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, −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) | His41, Met49, Tyr54, Lys137, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, Cys148, Met49, His163, Met165, Glu166, Leu167, Pro168, Asp187, Gln189, Gln192, Thr199, Tyr239, Tyr273, Leu275 Leu286, Leu287 | [31,57] |
| Tannins Phenylpropanoids Aromatic alcohol |
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 and −7.9 BE), tinosporide (2 HB, 12 NBI and −8.5 BE), chebulagic acid (6 HB, 3 NBI and −6.5 BE), chebulinic acid (9 HB, 9 NBI and −8.6 BE), gallotannins (5 HB, 10 NBI and −8.3 BE), cinnamtannin-B1 (3 HB, 4 HP and −8.4 BE), barlerinoside (7 HB, 10 NBI and −7.5 BE) Hydroxycinnamic acid (3 HB, 2A, 1 PA, and −7.5 BE) Phenethyl alcohol (6 HB, 2 PA, −7.3 BE) |
Thr24, Thr25, Thr26, His41, Cys44, Thr45, Ser46, Tyr54, Cys145, His163, Thr25, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His164, Met165, Glu166, His172, Ala285, Asp187, Arg188, Gln189, Asp197, Thr199, Tyr239, Met276, Leu287, Leu286 His41, His164, Gln192, Thr190, Pro168, Met165, Arg188, Arg187, Val186, Thr190, Gln192, Met49, Met165, Pro168 |
[[41], [56], [66]] [51] [51] |
| Standards |
N3 inhibitor (native cocrystal ligand) (8 HB, 6 HPI and −7.9 BE/28 IR and −9.47 BE/23 IR and −8.12 BE), nelfinavir (9 IR and −12.20 BE); prulifloxacin (10 IR and −11.32 BE) and colistin (18 IR and −13.73 BE), x77 (4 HB, 2 PS, 1 Pal, 1 Pam, 1 PP and −8.4 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), l X77 (4 HB, 2 PS, 1 PA1, 1 Pam, 1 PP and −8.4 BE) |
Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Glua47, Met49, Leu50, Pro52, Tyr54, Val104, Gln110, Ile106, Asp153, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, Ser158, His163, His164, Met165, Glu166, Leu167, Pro168, Gly170, Hie172, Asp187, Arg188, Gln189, Thr190, Ala191, Gln192, Val202, Ile249, Pro293, Phe294 Val297. |
[[20], [27], [31], [67], [73], [84], [109]] |
|
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), quercetin-7-O-glucuronide (6 HB, 1 PA and −8.2 BE), quercetin-3′-O-glucuronide (5 HB; 1 PAm; −8.2 BE), quercetin-3-O-glucuronide (6 HB; 2 PA; 1 Pal; −8.0 BE), quercetin-7-O-sulfate (6 HB, 1 PC, 1 Pal, and −8.0 BE), quercetin-3-O-sulfate (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) | Asp452, Lys545, Arg553, Ala554, Arg555, Thr556, Met615, Trp617, Asp618, Tyr619, Pro620, Lys621, Cys622, Asp623, Arg624, Thr687, Asn691, Ser759, Asp760, Asp761, Ser778, Ile779, Glu796, Lys798, Cys799, Trp800, Thr801, Glu811, Cys813, Ser814 | [20] |
| 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), 7-Deacetyl-7-benzoylgedunin (1 HB, 1 Alkyl/pi-alkyl, 2 CHB, 1 pi-anion, 3 pi-cation, 6 VDW and −8.2 BE), limonin glucoside (3 HB, 1 CHB, 4 Alkyl/Pi-Alkyl, 9 VDW and −8.2 BE), 7- -deacetylgedunin (1 HB, 2 CHB, 1 Pi-Alkyl, 1 Pi-sigma, 1 Pi-anion, 5 VDW and −8.1 BE), obacunone (2 HB, 1 Alkyl, 1 Pi-Anion, 8 VDW and −7.8 BE) | His439, Asp452, Tyr456, Met542, Lys545, Ala547, Ile548, Ser 549, Ala550, Lys551, Arg553, Ala554, Arg555, Thr556, Val557, Ala558, Gly616, Trp617, Asp618, Tyr619, Pro620, Cys622, Asp623, Arg624, Ser682, Asp760, Asp761, Ala762, Val763, Ala797, Lys798, Trp800, His810, Glu 811, Phe812, Ser814, Arg836 | [87] |
| 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) | |||
| Class |
Small molecule inhibitors |
Interacting residues with different classes of phytocompounds |
References |
| Flavonoids | Tomentodiplacone B (9 IR and −8.4 BE), osajin (4 IR and −8.2 BE), sesquiterpene glycoside (9 IR and −8.2 BE), rhamnetin (9 IR and −8.1 BE), silydianin (6 IR and −8.1 BE) | Val6, Asn9, Arg21, Arg22, Pro23, Phe24, Glu128, Arg129, Leu132, Phe133, Glu136, Arg178, Asn179, Pro234, Pro238, Ser310, Pro406, Ala407, Pro408, Asp534, Arg560 | [46] |
| Standards |
Nelfinavir (6 IR and −6.2 BE), remdesivir (8 IR and −6.8 BE), prulifloxacin (7 IR and −8.1 BE) |
Val6, Arg21, Arg129, Leu132, Glu136, Lys139, Glu142, Asn177, Asn179, Tyr180, Pro234, Pro238, Cys309, Met378, Asp383, Pro406, Ala407, Pro408, Arg409, Thr410, Leu412, Leu417, Arg560 |
[46] |
|
Endoribonuclease/nsp15 (viral protein) | |||
| Class |
Small molecule inhibitors |
Interacting residues with different classes of phytocompounds |
References |
| Flavonoid | 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), rutin (5 IR and −7.8 BE), silymarin (IR and −8.0 BE). | His235, ASP240, Gln245, Gly248, His250, Lys290, Val292, Ser294, Val339, Glu 340, Thr341, Tyr343, Pro344, Leu346 | [106] |
| Beta-diketone | 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) | His235, Glu340, Thr341, His250, Lys290; Ser294, Gly248 | [73] |
| Terpenoid | Saikosaponin-V (8 HB, 9 HP and −8.35 BE), saikosaponin-U (8 HB, 8 HP and −7.27 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 (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). | Gly230, Ala232, Glu234, Hip235, Asp240, Gly245, Leu246, Gly247, Gly248, His250, Asn278, Lys290, Cys291, Val292, Cys293, Met331, Ala232, Trp333, Val339, Glu340, Thr341, Tyr343, Pro344, Leu346 | [[75], [106]] |
| Coumarin | Beta sitosterol (1 IR and −8.1 BE), gliotoxin (3 IR and −6.7 BE), psoralen (5 IR and −6.7 BE), 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 −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) | His235, Gly248, His250, Lys290, Val292, Cys293, Ser294, Thr341, Tyr343. | [106] |
| 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), reserpine (4 IR and −7.4) | His235, Thr341, Gly248, His250, Lys290, Glu340 | [106] |
| Steroids | Asparoside-C (5 HB and −7.16 BE), asparoside-F (7 HB and −6.6 BE), asparoside-D (6 HB and −6.4 BE), rutin (5 HB), racemoside-A (4 HB and −5.99) | Gly230, Ala232, Glu234, Hip235, Val339, Asp240, His243, Gln245, His250, Asn278, Val292, Glu340, Thr341, Leu346 | [16] |
| Standards |
Hydroxychloroquine (4 IR and −5.8 BE), Nelfinavir (4 IR and −7.3 BE), ribavirin (9 IR and −5.84) |
Thr26, His235, His250, Gly248, Lys290, Val-292, Ser294, Thr341, Tyr 343, Pro344, |
[[73], [106]] |
|
2′-O- methyl transferase/nsp16 (viral protein) | |||
| Class |
Small molecule inhibitors |
Interacting residues with different classes of phytocompounds |
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 (8 IR and −8.2 BE) | Asp6873, Asn6899, Asp6897, Amet6929, Leu6898, Asn6841, 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. | [46] |
| Standards | Nelfinavir (9 IR and −8.2 BE), remdesivir (9 IR and −7.0 BE), prulifloxacin (12 IR and −7.6 BE) | Leu6898, Tyr6930, Gly6871, Pro6932, Lys6968, Lys6844, 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 | [46] |
Note: BE - binding energy, HB - hydrogen bond, HP/HPI - hydrophobic interactions, NBI = non-bonding interactions, IR-interacting residues, EI- electrostatic interactions, 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.