Table 1.

Summary of several in silico, in vitro, and in vivo investigations carried out on NS chemical constituents against COVID-19.

NS Constituent Identified as Anti-COVID-19	Type of Study	Finding of the Study
Caryophyllene oxide, β-bisabolene	In silico	Molecular docking studies (PDB IDs: 6YHU, 6W4B, 6VXS, 6LU7, 7BTF 6LZG) revealed caryophyllene oxide to possess the highest binding affinity towards 3CLpro, NSP3, NSP9, and RdRp molecular targets in COVID-19. ACE-2 binding affinity of β-bisabolene and remdesivir was almost similar [56]
Dithymoquinone (DTQ)	In silico	The binding affinity (PDB ID: 6VW1) of DTQ on SARS-CoV-2-ACE-2 was better than chloroquine. It was found to be stable at the docked site in molecular dynamics simulation studies [57]
α-Hederin	In silico	α-Hederin was found to be a better inhibitor of RdRp (PDB ID: 6M71) than DTQ, nigellicine, and nigellidine [58]
DTQ	In silico	DTQ was found to be active against 3CLpro (PDB ID: 6LU7) and Nsp15 (PDB ID: 6VWW) targets [59]
α -Hederin, rutin, and nigellamine A2	In silico	α-Hederin, rutin, and nigellamine A2 were identified as potential inhibitors of SARS-CoV-2 proteins (PDB IDs: 6W9C, 6Y2E, 6M71, 6ZSL, 6W4B, 6VWW, 6M17, and 6VYO) related to RdRp, protease, and helicase [60]
Nigellidine	In silico and in vivo	Nigellidine showed a good affinity toward COVID-19 Nsp2 and IL1R proteins (PDB IDs: 6LU7, 6VSB, 1ITB, and 1P9M). Nigellidine in vivo study in rats showed antioxidant, hepato-protective, and anti-inflammatory activities [61]
α-Hederin	In silico	NS chemical constituents such as α-hederin, stigmasterol glucoside, nigellidine-4-O-sulfite, nigellidine, sterol-3-β-D-glucoside, DTQ, β-sitosterol were identified as potential inhibitors of main protease (Mpro) (PDB IDs: 6LU7). Nigllimine, nigellimine N-oxide, carvacrol, TQ, THQ, thymol, anthole, etc., showed weaker binding affinity than remdesivir, lopinavir, and nelfinavir. α-Hederin was identified as the most promising anti-COVID agent [62]
α-Hederin, THQ, and TQ	In silico	In molecular docking studies, α-hederin, THQ, and TQ were found to be efficiently binding to ACE-2 (PDB ID: 1R4L) of SARS-CoV-2 [63]
Nigellone	In silico	Nigellone (DTQ) upon molecular docking studies with four COVID-19 protein targets (spike glycoprotein, 3CLpro/Mpro (PDB ID: 6LU7), human ACE-2) was observed to bind more strongly than carvacrol, nigellicine, nigellidine, TQ, THQ, and thymol. Its binding affinity on other viral proteins (PDB IDs: 6LU7, 6VSB, and 6VX) was better than remdesivir and hydroxychloroquine [64]. This study also advocated further in vitro experiments to establish Nigellone as an anti-COVID-19 lead compound
Nigellidine	In silico	Nigellidine was exposed to prevent SARS-CoV-2 NSP3 replication/transcription. It also blocked the pro-inflammatory cytokines TNF R1 and TNF R2 and Fas-induced apoptotic death [55]
DTQ and THQ	In vitro	Cytotoxicity of DTQ and THQ was tested in VERO-E6 cells by MTT assay. HTQ presented anti-SARS-CoV-2 action at non-cytotoxic nanomolar concentration (IC50 = 23.15 ng/mL) while DTQ showed an IC50 of 275.2 ng/mL [65]
TQ	In Silico and in vitro	TQ is bound strongly to ACE-2 of SARS-CoV-2 (PDB ID: 6VW1). In vitro results showed it to inhibit SARS-CoV-2 pseudo particles infecting HEK293-ACE2 cells with IC50 of 4.999 μM and CC50 of 35.100 μM; SI = 7.02) [66]