Potent toxic effects of Taroxaz-104 on the replication of SARS-CoV-2 particles

Abstract

Polyphenolics and 1,3,4-oxadiazoles are two of the most potent bioactive classes of compounds in medicinal chemistry, since both are known for their diverse pharmacological activities in humans. One of their prominent activities is the antimicrobial/antiviral activities, which are much apparent when the key functional structural moieties of both of them meet into the same compounds. The current COVID-19 pandemic motivated us to computationally screen and evaluate our library of previously-synthesized 2-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazoles against the major SARS-CoV-2 protein targets. Interestingly, few ligands showed promising low binding free energies (potent inhibitory interactions/affinities) with the active sites of some coronaviral-2 enzymes, specially the RNA-dependent RNA polymerase (nCoV-RdRp). One of them was 5,5'-{5,5'-[(1 R ,2 R )-1,2-dihydroxyethane-1,2-diyl]bis(1,3,4-oxadiazole-5,2-diyl)}dibenzene-1,2,3-triol (Taroxaz-104), which showed significantly low binding energies (-10.60 and -9.10 kcal/mol) with nCoV-RdRp-RNA and nCoV-RdRp alone, respectively. These binding energies are even considerably lower than those of remdesivir potent active metabolite GS-443902 (which showed -9.20 and -7.90 kcal/mol with the same targets, respectively). Further computational molecular investigation revealed that Taroxaz-104 molecule strongly inhibits one of the potential active sites of nCoV-RdRp (the one with which GS-443902 molecule mainly interacts), since it interacts with at least seven major active amino acid residues of its predicted pocket. The successful repurposing of Taroxaz-104 has been achieved after the promising results of the anti-COVID-19 biological assay were obtained, as the data showed that Taroxaz-104 exhibited very significant anti-COVID-19 activities (anti-SARS-CoV-2 EC 50 = 0.42 μM) with interesting effectiveness against the new strains/variants of SARS-CoV-2. Further investigations for the development of Taroxaz-104 and its coming polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives as anti-COVID-19 drugs, through in vivo bioevaluations and clinical trials research, are urgently needed.

Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

“…Although proposed drugs and vaccine candidates were approved for emergency treatment of COVID-19, the FDA recommended a few drugs to help control the pandemic. But there is still a need to expand the number of potential drug candidates that could have higher efficacy and fewer side effects for the treatment of COVID-19 [ [10] , [11] , [12] , [13] ].…”

Teriflunomide: A possible effective drug for the comprehensive treatment of COVID-19

“…Teriflunomide molecule has much simpler structure with lower molecular weight and volume if it is compared to the structures of both used references. The highly-balanced flexibility of the uncomplicated structure of teriflunomide is crucially needed for outstanding and perfect positioning of the drug molecule to be extremely superimposable in the active binding pocket and cavity of the COVID-19 polymerase protein (i.e., required for the extreme lock-and-key positioning) ( Rabie, 2021e ). This, in turn, results in more proper and sufficient (i.e., potent) inhibition of the replication activities mediated or controlled by the SARS-CoV-2 RdRp.…”

“…The SARS-CoV-2 has sheaths that enfold around the RNA genome (virion, which is the whole virus, is round/oval, usually polymorphic, with a diameter of approximately 50–200 nm) ( Wu et al, 2020 ). Except for the promising investigational drugs, cyanorona-20, CoViTris2020, ChloViD2020, and Taroxaz-104, there is no specific and effective potent drug therapy successfully recognized for COVID-19 to date at the middle of 2021 ( Jiang et al, 2020 ; Rabie, 2021a , 2021b , 2021c , 2021d ; Rabie, 2021e ; Rabie, 2021f ).…”

Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp)

“…Polyphenols possess a wide range of health benefits and biological activities, including antioxidant [50], antitumoral [51], anti-inflammatory [52], and antiviral properties [53], the latter of which suggests that polyphenols may be useful in the battle against multiple viruses, even SARS-CoV-2 [27,[54][55][56][57][58][59][60][61][62]. In fact, numerous studies have shown that polyphenols exhibit antiviral effects by inhibiting DNA/RNA synthesis [63][64][65][66][67]. Our previous study also demonstrated that miquelianin, a flavonol glucuronide, can compete for the binding site of dATP on HIV-1 reverse transcriptase, inhibiting the viral DNA synthesis by interacting with the last nucleotide of the RNA chain and the binding residues of DNA polymerase [68].…”