COVID-19 Therapeutics: Computational Screenings Show A Variety Of Natural Phytochemicals Could Have Efficacy Against SARS-CoV-2 Including EGCG From Green Tea

COVID-19 Therapeutics:  In many drug repurposing and potential therapeutics studies, researchers first use computational screening platforms that involves models of the SARS-CoV-2 coronavirus in detail especially the binding sites of the spike proteins and to match molecular models of existing drugs, supplements, phytochemicals etc to see which have a greater affinity to bind to these sites, hence rendering the virus inactive or unable to bind to the human host cells and replicate.


 
Many models are already available online for researchers to access and they show in extreme detail  the “docking sites” or sites on the spike proteins that binds to human host cells. There are numerous of such docking sites with unique molecular properties and researchers using computational programmes have to identify therapeutic molecules that can effectively dock at those sites to render the SARS-CoV-2 inactive. Upon finding such candidates, typically the next step is to conduct vitro studies, animal studies before proceeding to human clinical trials.
 
In one interesting study conducted by Indian researchers from Era University in Lucknow, the team studied 18 natural dietary phytochemicals, nutraceuticals such as alpha-lipoic acid and also chloroquine and remdesivir interactions with the molecular docking sites of 7 identified spike proteins found on the surface of the SARS-CoV-2 coronavirus. https://www.researchsquare.com/article/rs-19560/v1
 
In the study the 18 dietary molecules studied were epigallocatechin gallate (EGCG), piperine, apigenin, curcumin, gingerol-[6], beta glucan, resveratrol, myricetin, quercetin, genistein, diadzein, alliin, allicin, sulphoraphane, phycocyanobillin, ferulic acid and alpha lipoic acid.
 
Some of these promising dietary molecules could be developed as therapeutic agents in the prevention and treatment of current COVID–19 disease. In previous studies, numerous dietary molecules such as curcumin, savinin and betulinic acid have been found to show inhibition of 2003 SARS-CoV in the range of 3–10 μM concentrations https://www.researchgate.net/publication/326915905_Discovering_Health_Benefits_of_Phytochemicals_with_Integrated_Analysis_of_the_Molecular_Network_Chemical_Properties_and_Ethnopharmacological_Evidence or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115900/
 
Another study also showed that, kaempferol, quercetin, luteolin–7-glucoside, demethoxycurcumin, naringenin, apigenin–7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate have been identified as significant anti-SARS-CoV agents with the help of also molecular docking studies. https://tmu.pure.elsevier.com/en/publications/specific-plant-terpenoids-and-lignoids-possess-potent-antiviral-a
 
Among these dietary molecules, epigallocatechin gallate (EGCG) which is found abundantly in green tea, was found as most active agent against COVID–19.
 
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EGCG showed highest binding affinity (–9.30kcal/mole) and lowest inhibition constant (0.152µM) for the  6y2e spike protein. Moreover, EGCG exhibited a strong molecular interaction with 6vw1 which is an important target of this new coronavirus. It showed highest binding affinity and lowest inhibition constant with –8.66 kcal/mole and 0.152µM values respectively. Further, EGCG displayed excellent interactions with 6vww wherein it showed highest binding affinity (–8.38 kcal/mole) with lowest inhibition constant at 0.724 µM concentration. Additionally, EGCG also exhibited good molecular interactions with SARS-CoV–2 proteins 6lu7, 6lvn, 6lxt, and 6vsb with the values of binding energies and inhibition constant as –6.99, –4.90, –7.57, –7.26 kcal/mole and 7.57, 255.95, 2.84, 4.75 µM concentrations. The computed activity of EGCG was found to be higher than that of both reference drugs, Remdesivir and Chloroquine.
 

Table : Molecular docking values of phytochemicals against target protein macromolecules

Phytochemicals		Targets Proteins; binding energy in kcal/mole (inhibition constant in µM)
		6lu7	6lvn	6lxt	6vsb	6vw1	6vww	6y2e
1	EGCG	-6.99 (7.57)	-4.90 (255.95)	-7.57 (2.84)	-7.26 (4.75)	-8.66 (0.451)	-8.38 (0.724)	-9.30 (0.152)
2	Curcumin	-6.04 (37.57)	-4.73 (340.89)	-5.50 (92.90)	-5.05 (197.96)	-7.13 (5.91)	-7.37 (3.96)	-7.39 (3.83)
3	Apigenin	-5.96 (43.03)	-3.71 (1.9x10-5)	-5.13 (1.74x10-5)	-5.98 (4.1x10-5)	-6.02 (38.69)	-6.48 (17.86)	-7.05 (6.76)
4	Beta Glucan	-5.96 (42.79)	-4.16 (889.95)	-5.06 (195.39)	-3.20 (4.4x10-5)	-6.44 (19.09)	-6.72 (11.86)	-7.05 (6.83)
5	Myricetin	-5.38 (114.10)	-3.70 (1.96x10-5)	-5.74 (62.01)	-6.14 (31.32)	-6.50 (17.16)	-6.57 (15.20)	-7.15 (5.79)
6	Quercetin	-5.29 (132.27)	-3.68 (2.02x10-5)	-5.73 (63.52)	-6.14 (31.32)	-6.59 (14.73)	-6.53 (16.36)	-6.77 (10.86)
7	Piperine	-5.16 (165.72)	-4.08 (1.02x10-5)	-5.40 (109.87)	-6.05 (36.85)	-5.64 (73.80)	-6.18 (29.44)	-6.40 (20.37)
8	Genistein	-5.03 (204.91)	-3.97 (1.24x10-5)	-5.68 (69.09)	-6.54 (16.04)	-6.35 (22.18)	-6.73 (11.70 )	-6.80 (10.32)
9	Diadzein	-4.86 (275.53)	-3.72 (1.89x10-5)	-5.21 (151.77)	-6.16 (30.34)	-5.96 (42.54)	-6.43 (19.50)	-6.05 (36.86)
10	Ferulic acid	-4.76 (322.26)	-2.79 (9.00x10-5)	-3.75 (1.80 x10-5)	-5.44 (103.05)	-3.74 (1.8x10-5)	-3.90 (1.3 x10-5)	-4.71 (355.68)
11	Alliin	-4.66 (385.74)	-3.90 (1.37x10-5)	-5.02 (210.26)	-4.57 (447.67)	-5.15 (168.32)	-4.07 (1.0 x10-5)	-5.68 (68.09)
12	Lipoic acid	-4.58 (439.80)	-1.90 (40.6x10-5)	-3.25 (4.16x10-5)	-4.93 (243.60)	-2.73 (9.9x10-5)	-3.38 (3.3 x10-5)	-3.59 (2.3x10-5)
13	Resveratrol	-4.20 (832.91)	-3.58 (2.38x10-5)	-4.32 (685.04)	-5.57 (82.09)	-5.26 (138.32)	-5.57 (83.02)	-5.54 (86.98)
14	Glucosamine	-4.06 (1.06x10-5)	-3.59 (2.32x10-5)	-5.26 (138.93)	-4.89 (262.36)	-6.77 (10.89)	-4.18 (862.43)	-4.70 (359.49)
15	Gingerol-[6]	-4.00 (1.16)	-2.23 (23.38)	-3.08 (50.56)	-4.46 (537.58)	-4.60 (425.87)	-4.57 (449.30)	-5.30 (130.87)
16	Sulforaphane	-3.74 (1.81x10-5)	-2.25 (22.3x10-5)	-3.11 (5.22x10-5)	-3.43 (3.0x10-5)	-3.46 (2.9x10-5)	-3.21 (4.4x10-5)	-4.21 (815.35)
17	Allicin	-3.46 (2.89x10-5)	-2.09 (29.4x10-5)	-3.20 (4.49x10-5)	-3.46 (2.92)	-3.07 (5.6x10-5)	-3.14 (5.0x10-5)	-3.63 (2.1x10-5)
18	PCB	+0.16, (Nil)	-3.12 (5.14x10-5)	-4.63 (4.05x10-5)	+11.3 (Nil)	-3.59 (2.3x10-5)	-6.14 (3.1x10-5)	-5.15 (1.6x10-5)
19	Remdesvir	-2.47 (15.4x10-5)	-2.68 (10.7x10-5)