Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

Sada, Mitsuru; Saraya, Takeshi; Ishii, Haruyuki; Okayama, Kaori; Hayashi, Yuriko; Tsugawa, Takeshi; Nishina, Atsuyoshi; Murakami, Koichi; Kuroda, Makoto; Ryo, Akihide; Kimura, Hirokazu

doi:10.3390/microorganisms8101610

Cited by 29 publications

(25 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Deep analysis of the computational interaction mode of cyanorona-20-RTP with SARS-CoV-2 RdRp reveals its significant resemblance with that of favipiravir-RTP with the same polymerase, since both ligands form hydrogen bonds and hydrophobic interactions with almost the same or close amino acid residues of the proposed active site of the polymerase (Sada et al 2020 ; Picarazzi et al 2020 ; Jena 2020 ) (Fig. 7 a,b).…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug

Rabie

2021

Chem. Pap.

View full text Add to dashboard Cite

Specific inhibition of the viral RNA-dependent RNA polymerase (RdRp) of the newly-emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising strategy for developing highly potent medicines for coronavirus disease 2019 (COVID-19). However, almost all of the reported viral RdRp inhibitors (either repurposed drugs or new antiviral agents) lack selectivity against the SARS-CoV-2 RdRp. Herein, I discovered a new favipiravir derivative, ( E )- N -(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). Based on the significant reduction in the in vitro SARS-CoV-2 replication/copies, strong computational cyanorona-20 ligand-RdRp protein interactions, and anti-RdRp activity of the parent favipiravir drug, SARS-CoV-2 inhibition is thought to be mediated through the coronaviral-2 RdRp inhibition. This promising selective anti-COVID-19 compound is also, to the best of our knowledge, the first bioactive derivative of favipiravir, the known antiinfluenza and antiviral drug. This new nucleoside analog was designed, synthesized, characterized, computationally studied (through pharmacokinetic calculations along with computational molecular modeling and prediction), and biologically evaluated for its anti-COVID-19 activities (through a validated in vitro anti-COVID-19 assay). The results of the biological assay showed that cyanorona-20 surprisingly exhibited very significant anti-COVID-19 activity (anti-SARS-CoV-2 EC 50 = 0.45 μM), and, in addition, it could be also a very promising lead compound for the design of new anti-COVID-19 agents. Cyanorona-20 is a new favipiravir derivative with promise for the treatment of SARS-CoV-2 infection. Graphic abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11696-021-01640-9.

show abstract

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug

Rabie

2021

Chem. Pap.

View full text Add to dashboard Cite

show abstract

“…5 a,b show that Taroxaz-104 interacts with one or more of the predicted active/allosteric pockets (domains and motifs) of the nCoV-RdRp in closer mode(s) of action to that of the reference GS-443902. Taroxaz-104 molecule strikes about 50% of the same active amino acid residues that GS-443902 interacts with in chain A of nCoV-RdRp complex structure, namely His256/Tyr265/Ile266/Lys267/Trp268/Pro322/Pro323, respectively, revealing another additional active/allosteric site(s) of the polymerase to the previously-suggested one known for favipiravir [ 45 , 46 ]. Taroxaz-104 binds to the previously-mentioned amino acids with much more stronger interactions than GS-443902, thus predictably exhibits better inhibitory binding interactions than this reference ligand.…”

Section: Resultsmentioning

confidence: 98%

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

Rabie

2021

Chemico-Biological Interactions

View full text Add to dashboard Cite

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.

show abstract

“…The high conservation observed in the RNA-binding residues of the RdRP indicates that there is no evidence of remdesivir resistant mutations as of October 31, 2020. Continued surveillance of contact residues for remdesivir 11 and other drug candidates targeting the RdRP 38 is necessary to effectively respond to potential drug resistance in the future.…”

Section: Discussionmentioning

confidence: 99%

Analysis of SARS-CoV-2 Mutations Over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA Polymerase

Kechris

et al. 2021

Preprint

View full text Add to dashboard Cite

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences for the spike proteins and RNA-dependent RNA polymerase proteins were downloaded from the GISAID database, aligned, and the variants identified. Polymorphisms in the protein sequence were investigated at the protein structural level and examined longitudinally in order to identify sequence and strain variants that are emerging over time. Our analysis revealed a group of variants in the spike protein and the polymerase complex that appeared in August, and account for around five percent of the genomes analyzed up to the last week of October. A structural analysis also facilitated investigation of several unique variants in the receptor binding domain and the N-terminal domain of the spike protein, with high-frequency mutations occurring more commonly in these regions. The identification of new variants emphasizes the need for further study on the effects of these mutations and the implications of their increased prevalence, particularly as these mutations may impact vaccine or therapeutic efficacy.

show abstract

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

Cited by 29 publications

References 34 publications

RETRACTED ARTICLE: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug

RETRACTED ARTICLE: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug

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

Analysis of SARS-CoV-2 Mutations Over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA Polymerase

Contact Info

Product

Resources

About