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1.
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
2.
Viruses ; 13(7)2021 06 22.
Article in English | MEDLINE | ID: covidwho-1403875

ABSTRACT

Mammarenaviruses are prevalent pathogens distributed worldwide, and several strains cause severe cases of human infections with high morbidity and significant mortality. Currently, there is no FDA-approved antiviral drugs and vaccines against mammarenavirus and the potential treatment option is limited to an off-label use of ribavirin that shows only partial protective effect and associates with side effects. For the past few decades, extensive research has reported potential anti-mammarenaviral drugs and their mechanisms of action in host as well as vaccine candidates. This review describes current knowledge about mammarenavirus virology, progress of antiviral drug development, and technical strategies of drug screening.


Subject(s)
Antiviral Agents/pharmacology , Arenaviridae/drug effects , Drug Development/methods , High-Throughput Screening Assays , A549 Cells , Animals , Arenaviridae/pathogenicity , Chlorocebus aethiops , Clinical Trials as Topic , Drug Repositioning , HEK293 Cells , Humans , Ribavirin/pharmacology , Vero Cells , Virus Replication/drug effects
3.
Viruses ; 13(4)2021 04 03.
Article in English | MEDLINE | ID: covidwho-1389536

ABSTRACT

Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium-revealed by the changing composition of the mutant spectrum-may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed.


Subject(s)
Hepacivirus/genetics , Hepacivirus/physiology , Hepatitis C/virology , Antiviral Agents/pharmacology , COVID-19 , Cell Line , Drug Resistance, Viral/drug effects , Hepacivirus/drug effects , Humans , Mutation , RNA, Viral , Ribavirin/pharmacology , Sequence Analysis , Viral Nonstructural Proteins/genetics , Virus Replication/drug effects
4.
Mol Divers ; 26(1): 279-292, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1148916

ABSTRACT

Since the outbreak emerged in November 2019, no effective drug has yet been found against SARS-CoV-2. Repositioning studies of existing drug molecules or candidates are gaining in overcoming COVID-19. Antiviral drugs such as remdesivir, favipiravir, ribavirin, and galidesivir act by inhibiting the vital RNA polymerase of SARS-CoV-2. The importance of in silico studies in repurposing drug research is gradually increasing during the COVID-19 process. The present study found that especially ribavirin triphosphate and galidesivir triphosphate active metabolites had a higher affinity for SARS-CoV-2 RNA polymerase than ATP by molecular docking. With the Molecular Dynamics simulation, we have observed that these compounds increase the complex's stability and validate the molecular docking results. We also explained that the interaction of RNA polymerase inhibitors with Mg++, which is in the structure of NSP12, is essential and necessary to interact with the RNA strand. In vitro and clinical studies on these two molecules need to be increased.


Subject(s)
COVID-19 , Ribavirin , Adenine/analogs & derivatives , Adenosine/analogs & derivatives , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides , Antiviral Agents/chemistry , COVID-19/drug therapy , Drug Repositioning , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pyrazines , Pyrrolidines , RNA, Viral , Ribavirin/pharmacology , SARS-CoV-2
5.
Can J Physiol Pharmacol ; 99(5): 449-460, 2021 May.
Article in English | MEDLINE | ID: covidwho-1125455

ABSTRACT

Ribavirin is a guanosine analog with broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico, and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection, whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that ribavirin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, ribavirin was shown to decrease the expression of TMPRSS2 at both mRNA and protein levels 48 h after treatment. The suppressive effect of ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that ribavirin also showed an inhibitory effect on the TMPRSS2 enzyme. Based on these results, we hypothesized that ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effects of TMPRSS2 and ACE2 expression.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Down-Regulation/drug effects , Ribavirin/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Caco-2 Cells , Chlorocebus aethiops , G-Quadruplexes/drug effects , Humans , Promoter Regions, Genetic/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Vero Cells
6.
Viruses ; 13(2)2021 02 03.
Article in English | MEDLINE | ID: covidwho-1060766

ABSTRACT

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG's antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus OC43, Human/drug effects , Influenza A Virus, H1N1 Subtype/drug effects , Respiratory Syncytial Virus, Human/drug effects , SARS-CoV-2/drug effects , Thapsigargin/pharmacology , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Cell Line , Cell Line, Tumor , Cells, Cultured , Coronavirus OC43, Human/physiology , Endoplasmic Reticulum Stress , Humans , Influenza A Virus, H1N1 Subtype/physiology , Mice , Microbial Sensitivity Tests , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/virology , Respiratory Syncytial Virus, Human/physiology , Ribavirin/pharmacology , SARS-CoV-2/physiology , Thapsigargin/therapeutic use , Virus Replication/drug effects
7.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1030457

ABSTRACT

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , Chloroquine/pharmacology , Chloroquine/therapeutic use , Drug Combinations , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Immunization, Passive , Indoles/pharmacology , Indoles/therapeutic use , Interferons/pharmacology , Interferons/therapeutic use , Ivermectin/pharmacology , Ivermectin/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Nitro Compounds , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Purines/pharmacology , Purines/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thiazoles/pharmacology , Thiazoles/therapeutic use
8.
Viruses ; 13(1)2020 12 29.
Article in English | MEDLINE | ID: covidwho-1004758

ABSTRACT

RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in several cell models and rescued ZIKV-induced neurotoxicity in brain organoids. The compound's mechanism-of-action was pinpointed to late steps in the virus life cycle, impairing the formation of new virus particles. Collectively, in this study, we expand the antiviral activity of new small molecule inhibitors to a new virus class of Flaviviruses, but also uncover compounds' mechanism of action, which are important for the further development of antivirals.


Subject(s)
Antiviral Agents/pharmacology , Brain/metabolism , Organoids/metabolism , Zika Virus Infection/metabolism , Zika Virus/drug effects , Animals , Brain/pathology , COVID-19 , Cell Survival/drug effects , Humans , Organoids/pathology , RNA Viruses , Ribavirin/pharmacology , SARS-CoV-2 , Zika Virus/physiology , Zika Virus Infection/virology
9.
Sci Rep ; 10(1): 10100, 2020 06 22.
Article in English | MEDLINE | ID: covidwho-832425

ABSTRACT

RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two vaccines are available, the vaccination coverage of the equine population is largely insufficient to prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly inhibited viral replication and production of infectious particles. Since ribavirin is already approved in human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results open new perspectives for the management of EAV outbreaks.


Subject(s)
Arterivirus Infections/drug therapy , Equartevirus/metabolism , Ribavirin/pharmacology , Animals , Antiviral Agents/pharmacology , Arterivirus Infections/veterinary , Cell Line , Cytopathogenic Effect, Viral/drug effects , Horse Diseases/virology , Horses/genetics , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Purines/antagonists & inhibitors , Purines/biosynthesis , Purines/pharmacology , Pyrimidines/antagonists & inhibitors , Pyrimidines/biosynthesis , Pyrimidines/pharmacology , RNA/pharmacology , Virus Replication/drug effects , Virus Replication/physiology
10.
EMBO Mol Med ; 13(1): e13105, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-814824

ABSTRACT

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antiviral Agents/pharmacology , Benzamidines , Drug Repositioning/methods , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Guanine/pharmacology , Guanine/therapeutic use , Humans , Indoles/pharmacology , Indoles/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/physiology , Virus Internalization/drug effects , Virus Replication/drug effects
11.
J Nanosci Nanotechnol ; 20(12): 7311-7323, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-680345

ABSTRACT

We started a study on the molecular docking of six potential pharmacologically active inhibitors compounds that can be used clinically against the COVID-19 virus, in this case, remdesivir, ribavirin, favipiravir, galidesivir, hydroxychloroquine and chloroquine interacting with the main COVID-19 protease in complex with a COVID-19 N3 protease inhibitor. The highest values of affinity energy found in order from highest to lowest were chloroquine (CHL), hydroxychloroquine (HYC), favipiravir (FAV), galidesivir (GAL), remdesivir (REM) and ribavirin (RIB). The possible formation of hydrogen bonds, associations through London forces and permanent electric dipole were analyzed. The values of affinity energy obtained for the hydroxychloroquine ligands was -9.9 kcal/mol and for the chloroquine of -10.8 kcal/mol which indicate that the coupling contributes to an effective improvement of the affinity energies with the protease. Indicating that, the position chosen to make the substitutions may be a pharmacophoric group, and cause changes in the protease.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Adenine/administration & dosage , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/pharmacology , Adenosine/analogs & derivatives , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Amides/administration & dosage , Amides/chemistry , Amides/pharmacology , Antiviral Agents/administration & dosage , Binding Sites , COVID-19 , Chloroquine/administration & dosage , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus 3C Proteases , Drug Interactions , Humans , Hydrogen Bonding , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Ligands , Molecular Docking Simulation , Nanotechnology , Pandemics , Protease Inhibitors/administration & dosage , Pyrazines/administration & dosage , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrrolidines/administration & dosage , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Ribavirin/administration & dosage , Ribavirin/chemistry , Ribavirin/pharmacology , SARS-CoV-2 , Static Electricity
12.
Pathog Dis ; 78(4)2020 06 01.
Article in English | MEDLINE | ID: covidwho-646518

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5-7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Ribavirin/pharmacology , Saquinavir/pharmacology , Bronchoalveolar Lavage Fluid/chemistry , COVID-19 , Cell Degranulation/immunology , Endocytosis/immunology , Gene Expression Profiling , Humans , Lysosomes/immunology , Molecular Docking Simulation , Neutrophil Activation/immunology , Pandemics , SARS-CoV-2 , Transcriptome
13.
Int J Mol Sci ; 21(11)2020 May 30.
Article in English | MEDLINE | ID: covidwho-437471

ABSTRACT

The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease Mpro, because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2'-Fluoro-2'-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (-7.77 Kcal/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity -6.06 and -4.96 Kcal/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.


Subject(s)
Antiviral Agents/pharmacology , Cysteine Endopeptidases/chemistry , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry , Amides/chemistry , Amides/pharmacology , Amodiaquine/chemistry , Amodiaquine/pharmacology , Antiviral Agents/chemistry , Binding Sites , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Protease Inhibitors/chemistry , Protein Binding , Pyrazines/chemistry , Pyrazines/pharmacology , Ribavirin/chemistry , Ribavirin/pharmacology , Viral Nonstructural Proteins/metabolism
14.
Antiviral Res ; 178: 104786, 2020 06.
Article in English | MEDLINE | ID: covidwho-30820

ABSTRACT

An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 µM, 26.63 µM, 2.55 µM and 0.46 µM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 µM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 µM in combination with emetine at 0.195 µM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.


Subject(s)
Antimetabolites/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Emetine/pharmacology , Homoharringtonine/pharmacology , Lopinavir/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Virus Replication/drug effects , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/pharmacology , Animals , Betacoronavirus/physiology , COVID-19 , Chlorocebus aethiops , Drug Combinations , Epithelial Cells , Humans , Pandemics , Pyrazines/pharmacology , Ribavirin/pharmacology , SARS-CoV-2 , Vero Cells
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