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1.
Sci Rep ; 11(1): 23465, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1556248

ABSTRACT

Human coronavirus NL63 (HCoV-NL63) mainly affects young children and immunocompromised patients, causing morbidity and mortality in a subset of patients. Since no specific treatment is available, this study aims to explore the anti-SARS-CoV-2 agents including favipiravir and remdesivir for treating HCoV-NL63 infection. We first successfully modelled the 3D structure of HCoV-NL63 RNA-dependent RNA polymerase (RdRp) based on the experimentally solved SARS-CoV-2 RdRp structure. Molecular docking indicated that favipiravir has similar binding affinities to SARS-CoV-2 and HCoV-NL63 RdRp with LibDock scores of 75 and 74, respectively. The LibDock scores of remdesivir to SARS-CoV-2 and HCoV-NL63 were 135 and 151, suggesting that remdesivir may have a higher affinity to HCoV-NL63 compared to SARS-CoV-2 RdRp. In cell culture models infected with HCoV-NL63, both favipiravir and remdesivir significantly inhibited viral replication and production of infectious viruses. Overall, remdesivir compared to favipiravir is more potent in inhibiting HCoV-NL63 in cell culture. Importantly, there is no evidence of resistance development upon long-term exposure to remdesivir. Furthermore, combining favipiravir or remdesivir with the clinically used antiviral cytokine interferon-alpha resulted in synergistic effects. These findings provided a proof-of-concept that anti-SARS-CoV-2 drugs, in particular remdesivir, have the potential to be repurposed for treating HCoV-NL63 infection.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/chemistry , Antiviral Agents/chemistry , Coronavirus NL63, Human/enzymology , Pyrazines/chemistry , RNA-Dependent RNA Polymerase/chemistry , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Amides/metabolism , Amides/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Cell Culture Techniques , Cell Line , Coronavirus NL63, Human/physiology , Haplorhini , Humans , Molecular Docking Simulation , Pyrazines/metabolism , Pyrazines/pharmacology , RNA-Dependent RNA Polymerase/metabolism , Virus Replication/drug effects
2.
ChemMedChem ; 16(22): 3418-3427, 2021 11 19.
Article in English | MEDLINE | ID: covidwho-1525425

ABSTRACT

Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We have developed a set of pyrazine-based small molecules. A series of pyrazine conjugates was synthesized by microwave-assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR-CoV-2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine-triazole conjugates (5 d-g) and (S)-N-(1-(benzo[d]thiazol-2-yl)-2-phenylethyl)pyrazine-2-carboxamide 12 i show significant potency against SARS-CoV-2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir).


Subject(s)
Antiviral Agents/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/drug effects , Amides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/toxicity , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/metabolism , Pyrazines/toxicity , Quantitative Structure-Activity Relationship , Vero Cells
3.
Sci Rep ; 11(1): 19998, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462031

ABSTRACT

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/metabolism , Adenine/pharmacology , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Amides/adverse effects , Amides/metabolism , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/metabolism , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Chloroquine/pharmacology , Drug Design , Humans , Metabolic Networks and Pathways , Molecular Docking Simulation , Nitro Compounds/adverse effects , Nitro Compounds/metabolism , Nitro Compounds/pharmacology , Pyrazines/adverse effects , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Ribavirin/adverse effects , Ribavirin/metabolism , Ribavirin/pharmacology , SARS-CoV-2/metabolism , Thiazoles/adverse effects , Thiazoles/metabolism , Thiazoles/pharmacology
5.
J Phys Chem Lett ; 11(11): 4430-4435, 2020 Jun 04.
Article in English | MEDLINE | ID: covidwho-233085

ABSTRACT

The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs represent a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome SARS-CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.1% and 93.2% identity, respectively. Sequence alignment of six coronaviruses demonstrated higher identity among their RdRps (60.9%-98.1%) and lower identity among their Spike proteins (27%-77%). Thus, a 3D structural model of RdRp, NiRAN, non-structural protein 7 (nsp7), and nsp8 of SARS-CoV-2 was generated by modeling starting from the SARS counterpart structures. Furthermore, we demonstrate the binding poses of three viral RdRp inhibitors (Galidesivir, Favipiravir, and Penciclovir), which were recently reported to have clinical significance for SARS-CoV-2. The network of interactions established by these drug molecules affirms their efficacy to inhibit viral RNA replication and provides an insight into their structure-based rational optimization for SARS-CoV-2 inhibition.


Subject(s)
Betacoronavirus/enzymology , Nucleotidyltransferases/chemistry , RNA-Dependent RNA Polymerase/chemistry , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/metabolism , Adenosine/analogs & derivatives , Amides/chemistry , Amides/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Betacoronavirus/isolation & purification , Binding Sites , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Molecular Docking Simulation , Nucleotidyltransferases/metabolism , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Structure, Tertiary , Pyrazines/chemistry , Pyrazines/metabolism , Pyrrolidines/chemistry , Pyrrolidines/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2
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