scholarly journals Starting Anti-COVID-19 Drug Discovery with Natural Products

2021 ◽  
Vol 10 (1) ◽  
pp. 241-270
Author(s):  
OSMAR NASCIMENTO SILVA ◽  
Bruno Neves ◽  
Lucimar Rosseto ◽  
Rodrigo Moura ◽  
Hamilton Napolitano ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Rna Polymerase ◽  
Pegylated Interferon ◽  
Rna Dependent Rna Polymerase ◽  
Antiviral Effects ◽  
Frequent Mutations ◽  
Antiviral Activities ◽  
Underlying Mechanisms ◽  
High Infectivity

COVID-19 was characterized as a pandemic regarding its rapid international spread and severity on March 2020. The Coronaviridae family receives this name regarding the organization of the spike glycoprotein located in the envelope, which resembles a stellar corona when observed under a microscope. Coronaviruses undergo frequent mutations in their genome due to errors made by RNA-dependent RNA polymerase (RdRp). The SARS-CoV-2 was characterized by high infectivity and person to person transmission, with an incubation period of up to fourteen days. Potent antiviral activities of several natural products such as alkaloids, chalcones, triterpenoids have been reported but with unconfirmed efficacy or safety in the clinic as well as the complete underlying mechanisms. Also, CQ, HCQ and Ivermectin, remdesivir, lopinavir, ritonavir, favipiravir and pegylated interferon with ribavirin have been tested to develop both an effective therapy and a vaccine to treat COVID-19.  This study presents the antiviral effects of the natural products against SARS-CoV, HCoV-NL63, HCoV-229E and HCoV-OC43 showing that Lycorine, Emodin, Promazine, Saikosaponins B2, Silvestrol, Cepharanthine, Fangchinoline, Tetrandrine, Caffeic acid, Chlorogenic acid, Gallic acid and Emetine are a good candidates on treatment of coronaviruses infections.

scholarly journals Repurposing FDA-approved phytomedicines, natural products, antivirals and cell protectives against SARS-CoV-2 (COVID-19) RNA-dependent RNA polymerase

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10480
Author(s):  
Mahmoud Kandeel ◽  
Yukio Kitade ◽  
Abdullah Almubarak
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Rna Polymerase ◽  
Screening Assay ◽  
Rna Dependent Rna Polymerase ◽  
Recent Emergence ◽  
Essential Enzyme ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

Following the recent emergence of SARS-CoV-2 or coronavirus disease 2019 (COVID-19), drug discovery and vaccine design to combat this fatal infection are critical. In this study, an essential enzyme in the SARS-CoV-2 replication machinery, RNA-dependent RNA polymerase (RDRP), is targeted in a virtual screening assay using a set of 1,664 FDA-approved drugs, including sets of botanical and synthetic derivatives. A set of 22 drugs showed a high docking score of >−7. Notably, approximately one-third of the top hits were either from natural products or biological molecules. The FDA-approved phytochemicals were sennosides, digoxin, asiaticoside, glycyrrhizin, neohesperidin, taxifolin, quercetin and aloin. These approved natural products and phytochemicals are used as general tonics, antioxidants, cell protectives, and immune stimulants (nadid, thymopentin, asiaticoside, glycyrrhizin) and in other miscellaneous systemic or topical applications. A comprehensive analysis was conducted on standard precision and extra precision docking, two-step molecular dynamics simulations, binding energy calculations and a post dynamics analysis. The results reveal that two drugs, docetaxel and neohesperidin, showed strong binding profiles with SARS CoV-2 RdRP. These results can be used as a primer for further drug discovery studies in the treatment of COVID-19. This initiative repurposes safe FDA-approved drugs against COVID-19 RdRP, providing a rapid channel for the discovery and application of new anti-CoV therapeutics.

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.

Identifying Therapeutic Compounds Targeting RNA-Dependent-RNA-Polymerase of Sars-Cov-2

2020 ◽  
Author(s):  
Muhammad Roomi ◽  
Muhammad Mahmood ◽  
Yaser Khan
Keyword(s):  
Rna Polymerase ◽  
Field Analysis ◽  
Rna Dependent Rna Polymerase ◽  
Universal Force Field ◽  
Medicinal Use ◽  
Force Field Analysis ◽  
Electrostatic Potential Calculation ◽  
Antiviral Activities ◽  
Low Toxicity ◽  
Therapeutic Compounds

<p>COVID-19 emerged as the biggest threat of this century for mankind and later it spread across the globe through human to human transmission. Scientists rushed to understand the structure and mechanism of the virus so that antiviral drugs or vaccines to control this disease can be developed. A key to stop the progression of the disease is to inhibit the replication mechanism of Sars-Cov-2. RNA-dependent-RNA polymerase protein also called RdRp protein is the engine of Sars-Cov-2 that replicates the virus using viral RNA when it gains entry into the human cell. Numerous drugs proposed for the treatment of COVID-19 such as Camostat Mesylate, Remdesivir, Famotidine, Hesperidin, etc. are under trial to analyze the aftermath of their medicinal use. Nature is enriched with compounds that have antiviral activities and can potentially play a pivotal role to inhibit this virus. This study focuses on the phytochemicals that have the potential to exhibit antiviral activities. A large number of compounds were screened and a cohort of most suitable ones are suggested via in-silico techniques which are used worldwide for drug discovery such as docking, binding analysis, Universal Force Field Analysis, Broyden-Fletcher-Goldfarb-Shanno (BFGS) Method, Molecular Dynamic Simulation, and Electrostatic Potential Calculation. The proposed compounds are naturally occurring substances with low toxicity, very few side effects, proven anti-pathogenic effects, and most importantly are easily available.</p>

scholarly journals Identifying Therapeutic Compounds Targeting RNA-Dependent-RNA-Polymerase of Sars-Cov-2

2020 ◽  
Author(s):  
Muhammad Roomi ◽  
Muhammad Mahmood ◽  
Yaser Khan
Keyword(s):  
Rna Polymerase ◽  
Field Analysis ◽  
Rna Dependent Rna Polymerase ◽  
Universal Force Field ◽  
Medicinal Use ◽  
Force Field Analysis ◽  
Electrostatic Potential Calculation ◽  
Antiviral Activities ◽  
Low Toxicity ◽  
Therapeutic Compounds

<p>COVID-19 emerged as the biggest threat of this century for mankind and later it spread across the globe through human to human transmission. Scientists rushed to understand the structure and mechanism of the virus so that antiviral drugs or vaccines to control this disease can be developed. A key to stop the progression of the disease is to inhibit the replication mechanism of Sars-Cov-2. RNA-dependent-RNA polymerase protein also called RdRp protein is the engine of Sars-Cov-2 that replicates the virus using viral RNA when it gains entry into the human cell. Numerous drugs proposed for the treatment of COVID-19 such as Camostat Mesylate, Remdesivir, Famotidine, Hesperidin, etc. are under trial to analyze the aftermath of their medicinal use. Nature is enriched with compounds that have antiviral activities and can potentially play a pivotal role to inhibit this virus. This study focuses on the phytochemicals that have the potential to exhibit antiviral activities. A large number of compounds were screened and a cohort of most suitable ones are suggested via in-silico techniques which are used worldwide for drug discovery such as docking, binding analysis, Universal Force Field Analysis, Broyden-Fletcher-Goldfarb-Shanno (BFGS) Method, Molecular Dynamic Simulation, and Electrostatic Potential Calculation. The proposed compounds are naturally occurring substances with low toxicity, very few side effects, proven anti-pathogenic effects, and most importantly are easily available.</p>

scholarly journals Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

2020 ◽  
Author(s):  
Qi Liu ◽  
Amita Gupta ◽  
Ayse Okesli-Armlovich ◽  
Wenjie Qiao ◽  
Curt R. Fischer ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Antiviral Agent ◽  
Dihydroorotate Dehydrogenase ◽  
Rna Dependent Rna Polymerase ◽  
New Host ◽  
Genome Wide ◽  
Pyrimidine Salvage ◽  
Antiviral Activities ◽  
Salvage Pathways ◽  
Targeting Strategy

AbstractGenome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase (DHODH) as its target, along with the discovery that knockdown of genes in pyrimidine salvage pathways sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was efficiently converted into its triphosphates in cells. When combined with GSK983, it led to large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral genome infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activities of RdRp inhibitors.

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