scholarly journals In Silico Discovery of Natural Products Against Dengue RNA-Dependent RNA Polymerase Drug Target

2021 ◽  
Vol 21 (0) ◽  
pp. 11-27
Author(s):  
Junie B. Billones ◽  
Nina Abigail B. Clavio
Keyword(s):  
Natural Products ◽  
Rna Polymerase ◽  
In Silico ◽  
Drug Target ◽  
Rna Dependent Rna Polymerase

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals In silico study indicates antimalarials as direct inhibitors of SARS-CoV-2-RNA dependent RNA polymerase

2021 ◽  
pp. 1-18
Author(s):  
Pawan Kumar Doharey ◽  
Vishal Singh ◽  
Mallikarjuna Rao Gedda ◽  
Amaresh Kumar Sahoo ◽  
Pritish Kumar Varadwaj ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
In Silico Study ◽  
Direct Inhibitors

scholarly journals Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Sakshi Piplani ◽  
Puneet Kumar Singh ◽  
David A. Winkler ◽  
Nikolai Petrovsky
Keyword(s):  
Natural Products ◽  
Rna Polymerase ◽  
Kinase Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Rna Dependent Rna Polymerase ◽  
Starting Point ◽  
Potential Activity ◽  
Repurposed Drugs ◽  
Multiple Drugs

AbstractRepurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with diverse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp.

scholarly journals In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials

2020 ◽  
Author(s):  
Seref Gul ◽  
Onur Ozcan ◽  
sinan asar ◽  
Alper Okyar ◽  
Ibrahim Barıs ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Rna Polymerase ◽  
Protein Interactions ◽  
In Silico ◽  
Cost Effective ◽  
Md Simulations ◽  
Viral Rna ◽  
Free Energies ◽  
Rna Dependent Rna Polymerase ◽  
Approved Drugs

<p></p><p>Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxyquinoline. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL<sup>pro</sup>) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL<sup>pro</sup> based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.</p><br><p></p>

scholarly journals Potential RNA-dependent RNA polymerase inhibitors as prospective therapeutics against SARS-CoV-2

2020 ◽  
Vol 69 (6) ◽  
pp. 864-873 ◽  
Author(s):  
Rudramani Pokhrel ◽  
Prem Chapagain ◽  
Jessica Siltberg-Liberles
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Species Barrier ◽  
Rna Dependent Rna Polymerase ◽  
Virtual Screen ◽  
The Us ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics. Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication. Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen. Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects. Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

scholarly journals Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1166
Author(s):  
Krishnaprasad Baby ◽  
Swastika Maity ◽  
Chetan H. Mehta ◽  
Akhil Suresh ◽  
Usha Y. Nayak ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Active Site ◽  
In Silico ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Rna Dependent Rna Polymerase ◽  
Target Proteins ◽  
Dynamics Simulations ◽  
Preclinical And Clinical Studies ◽  
And Control

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (Mpro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.

scholarly journals Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Syed Ovais Aftab ◽  
Muhammad Zubair Ghouri ◽  
Muhammad Umer Masood ◽  
Zeshan Haider ◽  
Zulqurnain Khan ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Drug Target ◽  
Computational Approach ◽  
Therapeutic Drug ◽  
Rna Dependent Rna Polymerase
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