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Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain
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 princ...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Elsevier B.V.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282935/ https://www.ncbi.nlm.nih.gov/pubmed/34305173 http://dx.doi.org/10.1016/j.molstruc.2021.131106 |
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author | Rabie, Amgad M. |
author_facet | Rabie, Amgad M. |
author_sort | Rabie, Amgad M. |
collection | PubMed |
description | 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 EC(50) = 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., preclinical/clinical trials, are pressingly required. |
format | Online Article Text |
id | pubmed-8282935 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier B.V. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82829352021-07-20 Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain Rabie, Amgad M. J Mol Struct Article 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 EC(50) = 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., preclinical/clinical trials, are pressingly required. Elsevier B.V. 2021-12-15 2021-07-16 /pmc/articles/PMC8282935/ /pubmed/34305173 http://dx.doi.org/10.1016/j.molstruc.2021.131106 Text en © 2021 Elsevier B.V. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Rabie, Amgad M. Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain |
title | Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain |
title_full | Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain |
title_fullStr | Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain |
title_full_unstemmed | Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain |
title_short | Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain |
title_sort | discovery of taroxaz-104: the first potent antidote of sars-cov-2 voc-202012/01 strain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282935/ https://www.ncbi.nlm.nih.gov/pubmed/34305173 http://dx.doi.org/10.1016/j.molstruc.2021.131106 |
work_keys_str_mv | AT rabieamgadm discoveryoftaroxaz104thefirstpotentantidoteofsarscov2voc20201201strain |