scholarly journals Rationale Based Selection and Prioritization of Antiviral Drugs for COVID-19 Management

2020 ◽  
Author(s):  
Rakesh Joshi ◽  
Ashok P. Giri ◽  
Mahesh J. Kulkarni ◽  
mahesh gupta ◽  
Savita Verma ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Drugs ◽  
Drug Combinations ◽  
Proteolytic Processing ◽  
Therapeutic Interventions ◽  
Investigational Drug ◽  
Main Protease ◽  
Specific Proteins ◽  
Viral Polyprotein ◽  
Selection Of

<div>Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5</div><div>million individuals with around 0.35 million deaths worldwide till May 2020 end. Several</div><div>efforts are on in search of therapeutic interventions, but the preferred way is drug</div><div>repurposing due to the feasibility and urgency of the situation. To select and prioritize</div><div>approved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs having</div><div>proven safety profile in humans were subjected to virtual screening for binding to three</div><div>select targets namely human angiotensin-converting enzyme receptor-2 receptor-binding</div><div>domain (hACE-2) involved in virus entry, SARS-CoV-2 RNA dependent RNA polymerase</div><div>(RdRp) responsible for viral RNA replication and SARS-CoV-2 main protease (MPro) causing</div><div>proteolytic processing of viral polyprotein slab. Targeting multiple ‘disease pathogenesis</div><div>specific proteins’ within a close network of interaction or having dependent functionality can</div><div>provide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine and</div><div>Indinavir were identified as candidate drugs of interest for COVID-19 based on a derived</div><div>combined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir and</div><div>Daclatasvir and their approved marketed combination with Sofosbuvir emerged as leading</div><div>candidate drugs/drug combinations for SARS-CoV-2. These candidates have the potential</div><div>for the antiviral activity for SARS-CoV-2 infection better than the investigational drug</div><div>Remdesivir and other antiviral drugs/drug combinations being evaluated. These</div><div>drugs/combinations merit systematic fast track preclinical and clinical evaluation for COVID-</div><div>19 management. The present work brings back attention to the potential usefulness of</div><div>approved antiviral drugs/drug combinations, commonly available with established safety</div><div>profile, currently not in focus for COVID-19. It provides a rationale based approach for the</div><div>selection of drugs with potential antiviral activity against SARS-CoV-2 highlighting the</div><div>desired properties.</div>

scholarly journals Rationale Based Selection and Prioritization of Antiviral Drugs for COVID-19 Management

2020 ◽  
Author(s):  
Rakesh Joshi ◽  
Ashok P. Giri ◽  
Mahesh J. Kulkarni ◽  
mahesh gupta ◽  
Savita Verma ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Drugs ◽  
Drug Combinations ◽  
Proteolytic Processing ◽  
Therapeutic Interventions ◽  
Investigational Drug ◽  
Main Protease ◽  
Specific Proteins ◽  
Viral Polyprotein ◽  
Selection Of

<div>Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5</div><div>million individuals with around 0.35 million deaths worldwide till May 2020 end. Several</div><div>efforts are on in search of therapeutic interventions, but the preferred way is drug</div><div>repurposing due to the feasibility and urgency of the situation. To select and prioritize</div><div>approved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs having</div><div>proven safety profile in humans were subjected to virtual screening for binding to three</div><div>select targets namely human angiotensin-converting enzyme receptor-2 receptor-binding</div><div>domain (hACE-2) involved in virus entry, SARS-CoV-2 RNA dependent RNA polymerase</div><div>(RdRp) responsible for viral RNA replication and SARS-CoV-2 main protease (MPro) causing</div><div>proteolytic processing of viral polyprotein slab. Targeting multiple ‘disease pathogenesis</div><div>specific proteins’ within a close network of interaction or having dependent functionality can</div><div>provide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine and</div><div>Indinavir were identified as candidate drugs of interest for COVID-19 based on a derived</div><div>combined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir and</div><div>Daclatasvir and their approved marketed combination with Sofosbuvir emerged as leading</div><div>candidate drugs/drug combinations for SARS-CoV-2. These candidates have the potential</div><div>for the antiviral activity for SARS-CoV-2 infection better than the investigational drug</div><div>Remdesivir and other antiviral drugs/drug combinations being evaluated. These</div><div>drugs/combinations merit systematic fast track preclinical and clinical evaluation for COVID-</div><div>19 management. The present work brings back attention to the potential usefulness of</div><div>approved antiviral drugs/drug combinations, commonly available with established safety</div><div>profile, currently not in focus for COVID-19. It provides a rationale based approach for the</div><div>selection of drugs with potential antiviral activity against SARS-CoV-2 highlighting the</div><div>desired properties.</div>

scholarly journals Ebselen, disulfiram, carmofur, PX-12, tideglusib, and shikonin are non-specific promiscuous SARS-CoV-2 main protease inhibitors

2020 ◽  
Author(s):  
Chunlong Ma ◽  
Yanmei Hu ◽  
Julia Alma Townsend ◽  
Panagiotis I. Lagarias ◽  
Michael Thomas Marty ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Drug Targets ◽  
Cysteine Proteases ◽  
Native Mass Spectrometry ◽  
Main Protease ◽  
Enterovirus A71 ◽  
Dynamics Simulations ◽  
Hit Validation ◽  
Viral Polyprotein ◽  
Inhibition Potency

AbstractThere is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the viral main protease (Mpro) is one of the most extensively studied drug targets. Mpro is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites and it is highly conserved among coronaviruses. In addition, Mpro has a unique substrate preference for glutamine in the P1 position. Taken together, it appears that Mpro inhibitors can achieve both broad-spectrum antiviral activity and a high selectivity index. Structurally diverse compounds have been reported as Mpro inhibitors, with several of which also showed antiviral activity in cell culture. In this study, we investigated the mechanism of action of six previously reported Mpro inhibitors, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 using a consortium of techniques including FRET-based enzymatic assay, thermal shift assay, native mass spectrometry, cellular antiviral assays, and molecular dynamics simulations. Collectively, the results showed that the inhibition of Mpro by these six compounds is non-specific and the inhibition is abolished or greatly reduced with the addition of reducing reagent DTT. In the absence of DTT, these six compounds not only inhibit Mpro, but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease, the 2Apro and 3Cpro from enterovirus A71 (EV-A71) and EV-D68. However, none of the compounds inhibits the viral replication of EV-A71 or EV-D68, suggesting that the enzymatic inhibition potency IC50 values obtained in the absence of DTT cannot be used to faithfully predict their cellular antiviral activity. Overall, we provide compelling evidence suggesting that ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 are non-specific SARS-CoV-2 Mpro inhibitors, and urge the scientific community to be stringent with hit validation.

scholarly journals Drug repurposing and polypharmacology to fight SARS-CoV-2 through the inhibition of the main protease

2020 ◽  
Author(s):  
Luca Pinzi ◽  
Annachiara Tinivella ◽  
Fabiana Caporuscio ◽  
Giulio Rastelli
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Therapeutic Indication ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Selection Of

Abstract Therapeutic options are urgently needed to fight the outbreak of a novel coronavirus (SARS-CoV-2), which causes the COVID-19 disease and is spreading rapidly around the world. Drug repurposing can significantly accelerate the identification of drug candidates suitable for clinical evaluation. Moreover, polypharmacological effects may increase antiviral activity and/or counteract severe complications concurrently affecting COVID-19 patients. Herein, we present the results of a computational drug repurposing campaign in search of potential inhibitors of the main protease of SARS-CoV-2. The screening allowed the selection of 22 promising drugs. Some of them have already entered clinical trials, but the vast majority of the identified compounds are new and have never been considered before. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

In silico screening of phytoconstituents with antiviral activities against SARS-COV-2 main protease, Nsp12 polymerase and Nsp13 helicase proteins

2021 ◽  
Vol 18 ◽  
Author(s):  
Jainey James ◽  
Divya Jyothi ◽  
Sneh Priya
Keyword(s):  
Antiviral Activity ◽  
Molecular Interactions ◽  
In Silico ◽  
Antiviral Treatment ◽  
In Vivo Studies ◽  
Main Protease ◽  
Hypothesis Model ◽  
Antiviral Activities ◽  
Pharmacophore Hypothesis

Aims: The present study aim was to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies was molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop and phase application of Schrodinger respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor, online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) as excellent products to bind with their respective targets such as 6LU7, 6M71 and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside have well-interacted with all the three proteins, and these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and in-vivo studies could be carried out to provide better drug therapy.

Search for active candidates in a range of flavonoids regarding SARS-CoV-2 by the method of molecular docking

2021 ◽  
pp. 22-35
Author(s):  
Stanislav V. Pechinskii ◽  
Eduard T. Oganesyan ◽  
Anna G. Kuregyan
Keyword(s):  
Molecular Docking ◽  
Antiviral Activity ◽  
Cost Effective ◽  
Structural Features ◽  
Biologically Active ◽  
Active Structures ◽  
Main Protease ◽  
Targeted Screening ◽  
The Relationship ◽  
Structure And Activity

Molecular docking is a convenient and cost-effective tool for targeted screening of biologically active structures. This method makes it possible to reveal the relationship between structure and activity, as well as to search for new active compounds. Due to the fact that the antiviral activity of flavonoids and their derivatives has been shown experimentally and clinically, the study of their antiviral activity against SARS-CoV-2 is a promising study. In an in silico experiment, the possibility of binding 20 flavonoid ligands and the main protease SARS-CoV-2 was studied. The structural features of flavone and flavanone derivatives have been determined, which determine their ability to block the main protease of the SARS-CoV-2 virus. Structures of eight new candidates that bind the main protease SARS-CoV-2, which have the prospect of synthesis and further pharmacological research, have been proposed.

Clinical use of Antiviral Drugs

1987 ◽  
Vol 21 (5) ◽  
pp. 399-405 ◽  
Author(s):  
Milap C. Nahata
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Antiviral Agent ◽  
Antiviral Drugs ◽  
Investigational Drug ◽  
Virus Infections ◽  
Herpes Encephalitis ◽  
Herpes Simplex Viruses ◽  
Varicella Zoster ◽  
Syncytial Virus

Remarkable progress has been made in antiviral chemotherapy. Six approved antiviral drugs are now available for the treatment of various viral infections. Trifluridine, idoxuridine and vidarabine are all effective in patients with herpes keratitis; trifluridine is preferred due to its low toxicity. Acyclovir is the drug of choice in patients with infections due to herpes simplex viruses, including genital herpes, herpes encephalitis, and neonatal herpes, and infections due to varicella-zoster virus. Amantadine is the only drug currently available for prophylaxis and treatment of influenza A, but an investigational drug, rimantadine, appears to be equally effective and less toxic than amantadine. Ribavirin is the most recently approved antiviral agent for the treatment of respiratory syncytial virus infections. Numerous antiviral drugs are being studied in patients with acquired immunodeficiency syndrome. Although currently available drugs have improved our ability to manage a variety of viral illnesses, much needs to be learned about specific dosage guidelines based on the studies of pharmacokinetics, pharmacodynamics, potential adverse effects and viral resistance, and the role of combination therapy to optimize therapy.

Connotative Meaning of Time in Therapists' Conceptualization of Psychotherapeutic Interventions

1993 ◽  
Vol 72 (3_suppl) ◽  
pp. 1211-1221
Author(s):  
Dawn S. O'Neil ◽  
Anthony F. Grasha
Keyword(s):  
Subjective Experience ◽  
Specific Treatment ◽  
Therapeutic Interventions ◽  
Semistructured Interview ◽  
Connotative Meaning ◽  
Treatment Interventions ◽  
Psychotherapeutic Interventions ◽  
Experience Of Time ◽  
Perception Of Time ◽  
Selection Of

This study examined the connotative meaning which beginner ( n = 15), intermediate ( n = 14), and advanced ( n = 15) therapists assigned to time in psychotherapy and their perception of time as a factor in designing therapeutic interventions. Therapists' conceptualization of the subjective experience of time as a component of psychotherapeutic interventions was assessed by examining their selection of metaphors for time, their semantic differential assessments of past, present, and future perspectives, and through their responses to a semistructured interview. Therapists at all three levels of experience appeared to view time for their clients as moving slowly, promoting growth, and allowing progress, with an emphasis on the importance of future time-based interventions for growth while the clients' past was viewed as reflective of distress. Responses appeared to be atheoretical and idiosyncratic, showing lack of clear integration of time with specific treatment interventions.

scholarly journals Identification of novel antiviral drug combinations in vitro and tracking their development

2020 ◽  
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yao ◽  
Svetlana Biza ◽  
Eva Zusinaite ◽  
Andres Männik ◽  
...  
Keyword(s):  
Viral Infections ◽  
Human Lung ◽  
Antiviral Drug ◽  
A549 Cells ◽  
Drug Combinations ◽  
Investigational Drug ◽  
Synergistic Activity ◽  
Lung Epithelial ◽  
Reduced Toxicity

AbstractCombination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

scholarly journals ACTIVITY SCREENING AND STRUCTURE MODIFICATION OF ARTOCARPIN AGAINST ACE2 AND MAIN PROTEASE THROUGH IN SILICO METHOD

2021 ◽  
pp. 192-198
Author(s):  
MUHAMMAD FAUZI ◽  
ARIS FADILLAH ◽  
FAUZI RAHMAN ◽  
JUWITA RAMADHANI ◽  
KARINA ERLIANTI ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
In Silico ◽  
Docking Simulation ◽  
Positive Control ◽  
Hydroxyl Group ◽  
Artocarpus Altilis ◽  
Main Protease ◽  
Activity Screening ◽  
The Stability ◽  
The Right

Objective: SARS-CoV-2 is a type of coronavirus that causes COVID-19 disease. Currently, the right and effective drug for the treatment of COVID-19 has not been found. Artocarpin in the breadfruit plant (Artocarpus altilis), which was tested, has been shown to have antiviral activity. However, artocarpin has a hydroxyl group that can undergo oxidation within a certain time, thereby reducing the stability of the compound and non-specific antiviral activity. Methods: In this study, the structural modification of artocarpin was carried out to obtain compounds with anticoronavirus activity with good physicochemical properties. This research was conducted in silico, including molecular docking simulation, bioavailability prediction, and preADMET. Results: The top 20 modified compounds were selected from each target's top 3 compounds, which had better bond energies compared to the positive control. These 3 compounds have the potential to inhibit ACE2 and Mpro receptors and 1 compound are better at inhibiting both. Conclusion: From the results of the research conducted, we conclude that the 3 best compounds can be potential candidates that can be developed as COVID-19 therapy.

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