Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain

• Published in: Journal of molecular structure 2021-12, Vol.1246, p.131106-131106, Article 131106
• Main Author: Rabie, Amgad M.
• Format: Article
• Language: English
• Subjects: 2,5-Disubstituted-1,3,4-oxadiazole agent; Anti-COVID-19 compound; Anti-VOC-202012/01 and anti-501.V2 activity; Coronaviral-2 RNA-dependent RNA polymerase (nCoV-RdRp); Coronavirus; Delta variant; Drug discovery; GS-443902 active metabolite; Indian COVID-19; New double mutant variant; Polyhydroxyphenol; Remdesivir molecule; SARS-CoV-2 variant; Taroxaz-104
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2021.131106

•SAR-CoV-2 polymerase enzyme (nCoV-RdRp) blockade is the most effective approach for COVID-19 therapy.•Taroxaz-104 is the first polyhydroxyphenolic oxadiazole with strong antiviral activities against the new SARS-CoV-2 strain VOC-202012/01.•Taroxaz-104 potently blocks nCoV-RdRp with considerably low inhibitory binding free energy of -10.60 kcal/mol.•Taroxaz-104 inhibits SARS-CoV-2 life cycle with significant minute EC50 value of 0.42 μM.•Taroxaz-104 compound has significantly high values of SI (>> 238.10) and CC50 (>> 100 μM). Polyhydroxyphenols and nitrogenous heterocyclics are two of the most powerful active species of molecules in pharmaceutical chemistry, as each of them is renowned for its various bioactivities for humans. One of their outstanding actions is the antiviral activities, which clearly appear if the principal functional entities of both classes meet into one compound. The recent COVID-19 pandemic pushed us to computationally sift and assess our small library of synthetic 2-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazoles against the main coronaviral protein/enzymatic targets. Surprisingly, few ligands exhibited interesting low binding energies (strong inhibitory affinities) with some SARS-CoV-2 proteins, mainly the pivotal enzyme RNA-dependent RNA polymerase (nCoV-RdRp). One of these compounds was Taroxaz-104 (5,5′-{5,5′-[(1R,2R)-1,2-dihydroxyethane-1,2-diyl]bis(1,3,4-oxadiazole-5,2-diyl)}dibenzene-1,2,3-triol), which presented lower binding free energies of about -10.60 and -9.10 kcal/mol (as compared to the reference agent, GS-443902, which presented about -9.20 and -7.90 kcal/mol) with nCoV-RdRp-RNA and nCoV-RdRp alone, respectively. Extensive molecular modeling examination disclosed the potent Taroxaz-104 inhibition of one of the possible active/allosteric sites of nCoV-RdRp, since Taroxaz-104 molecule interacts with at least seven main amino acids of the presumed pocket/cavity of this nCoV-RdRp active site. The effective repurposing of Taroxaz-104 molecule was attained after the satisfactorily interesting results of the anti-COVID-19 bioassay were secured, since these data demonstrated that Taroxaz-104 showed very efficient anti-COVID-19 actions (anti-SARS-CoV-2 EC50 = 0.42 μM) with specific promising efficacy against the new SARS-CoV-2 strains. Additional research studies for the progress of Taroxaz-104 and other related polyphenolic 2,5-disubstituted-1,3,4-oxadiazole analogs as successful anti-SARS-CoV-2 medications, via, e.g., preclinica