scholarly journals Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies

2020 ◽  
Author(s):  
Ananta Swargiary
Keyword(s):  
Rna Polymerase ◽  
3D Structure ◽  
Antiviral Drug ◽  
Strong Interactions ◽  
Therapeutic Drug ◽  
Binding Property ◽  
Binding Interaction ◽  
Rna Dependent Rna Polymerase ◽  
Potential Inhibitor ◽  
In Silico Studies

Abstract Purpose: COVID-19, caused by SARS-CoV2 virus is a contagious disease affecting millions of lives throughout the globe. Currently, there are no clinically approved drugs for SARS-CoV2 although some drugs are undergoing clinical trials. The present study investigates the binding property of ivermectin on four important drug targets, spike protein, RNA-dependent RNA polymerase, 3-chymotrypsin- and papain-like proteases of SARS-CoV2. Methods: The 3D structure of ivermectin along with known antiviral drug lopinavir, simeprevir and four nucleotides ATP, GTP, CTP, and UTP were downloaded from PubChem database. Crystal structures of proteins were downloaded from PDB database. PDB files were converted into pdbqt file using AutoDock tools. After proper processing and grid formation, docking was carried out in AutoDock vina. Furthermore, the co-crystallized RNA and its binding interactions with RdRp were studied using various visualization tools including Discovery studio.Results: Docking study showed that ivermectin is the best binding drug compared to lopinavir and simeprevir. The best binding interaction was found to be -9.7kcal/mol with RdRp suggesting potential inhibitor of the protein. Twenty-one amino acid residues of RdRp were found to interact with ivermectin including the catalytic residue Asp760. Furthermore, RNA-RdRp complex revealed that the catalytic active residues Ser759 and Asp760 of RdRp formed strong interactions with RNA chain. Binding of ivermectin in the active site of RdRp make clash with the nucleotides of RNA chain suggesting the possible inhibition of replication.Conclusions: The present study suggests ivermectin as a potential inhibitor of RdRp which may be crucial to combat the SARS-CoV2.

scholarly journals Plant-Derived Natural Polyphenols as Potential Antiviral Drugs Against SARS-CoV-2 via RNA‐dependent RNA Polymerase (RdRp) Inhibition: An In-Silico Analysis

2020 ◽  
Author(s):  
Satyam Singh ◽  
Avinash Sonawane ◽  
Sushabhan Sadhukhan
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Virus Type ◽  
Antiviral Drug ◽  
Effective Therapy ◽  
Therapeutic Drug ◽  
Therapeutic Effects ◽  
Rna Dependent Rna Polymerase ◽  
Dietary Polyphenols ◽  
Natural Polyphenols

<p>The sudden outburst of Coronavirus disease (COVID-19) has left the entire world to a standstill. COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As per the report from the WHO, more than 4.5 million people have been infected by SARS-CoV-2 with more than 3,00,000 deaths across the globe. As of now, there is no therapeutic drug or vaccine approved for the treatment of SARS-CoV-2 infection. Hence, the outbreak of COVID-19 poses a massive threat to humans. Due to the time taking process of new drug design and development, drug repurposing might be the only viable solution to tackle COVID-19. RNA‐dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication, <i>i.e.</i> the synthesis of single-stranded RNA genomes, an absolutely necessary step for the survival and growth of the virus. Thus, RdRp is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols have been shown to inhibit enzymatic activities of RdRp of various RNA viruses including polio-virus type 1, parainfluenza virus type 3, and respiratory syncytial virus etc. More importantly, natural polyphenols have been used as a dietary supplementation for humans for a long time and played a beneficial role in immune homeostasis. Therefore, we were curious to study the binding of dietary polyphenols with RdRp of SARS-CoV-2 and assess their potential as an effective therapy for COVID-19. In this present work, we made a library of twenty potent polyphenols that have shown substantial therapeutic effects against various diseases. The polyphenols were successfully docked in the catalytic pocket of RdRp of SARS-CoV and SARS-CoV-2, and detailed studies on ADME prediction, toxicity prediction and target analysis were performed. The study reveals that EGCG, quercetagetin, and myricetin strongly bind to the active site of SARS-CoV-2 RdRp. Our studies suggest that EGCG, quercetagetin, and myricetin can inhibit RdRp and represent an effective therapy for COVID-19. </p>

scholarly journals Plant-Derived Natural Polyphenols as Potential Antiviral Drugs Against SARS-CoV-2 via RNA‐dependent RNA Polymerase (RdRp) Inhibition: An In-Silico Analysis

2020 ◽  
Author(s):  
Satyam Singh ◽  
Avinash Sonawane ◽  
Sushabhan Sadhukhan
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Virus Type ◽  
Antiviral Drug ◽  
Effective Therapy ◽  
Therapeutic Drug ◽  
Therapeutic Effects ◽  
Rna Dependent Rna Polymerase ◽  
Dietary Polyphenols ◽  
Natural Polyphenols

<p>The sudden outburst of Coronavirus disease (COVID-19) has left the entire world to a standstill. COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As per the report from the WHO, more than 4.5 million people have been infected by SARS-CoV-2 with more than 3,00,000 deaths across the globe. As of now, there is no therapeutic drug or vaccine approved for the treatment of SARS-CoV-2 infection. Hence, the outbreak of COVID-19 poses a massive threat to humans. Due to the time taking process of new drug design and development, drug repurposing might be the only viable solution to tackle COVID-19. RNA‐dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication, <i>i.e.</i> the synthesis of single-stranded RNA genomes, an absolutely necessary step for the survival and growth of the virus. Thus, RdRp is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols have been shown to inhibit enzymatic activities of RdRp of various RNA viruses including polio-virus type 1, parainfluenza virus type 3, and respiratory syncytial virus etc. More importantly, natural polyphenols have been used as a dietary supplementation for humans for a long time and played a beneficial role in immune homeostasis. Therefore, we were curious to study the binding of dietary polyphenols with RdRp of SARS-CoV-2 and assess their potential as an effective therapy for COVID-19. In this present work, we made a library of twenty potent polyphenols that have shown substantial therapeutic effects against various diseases. The polyphenols were successfully docked in the catalytic pocket of RdRp of SARS-CoV and SARS-CoV-2, and detailed studies on ADME prediction, toxicity prediction and target analysis were performed. The study reveals that EGCG, quercetagetin, and myricetin strongly bind to the active site of SARS-CoV-2 RdRp. Our studies suggest that EGCG, quercetagetin, and myricetin can inhibit RdRp and represent an effective therapy for COVID-19. </p>

In silico studies of bacterial derived fatty acid as a potential inhibitor of 1FGE and 1BQO

2021 ◽  
Vol 16 (12) ◽  
pp. 119-124
Author(s):  
S. Syed Chandini ◽  
Sairam Mantri
Keyword(s):  
Ligand Binding ◽  
Stearic Acid ◽  
In Silico ◽  
In Vivo Studies ◽  
Binding Interaction ◽  
Standard Drug ◽  
Synthetic Drugs ◽  
Potential Inhibitor ◽  
In Silico Studies

Thrombomodulin (TM) and matrix metalloproteinase (MMPs) are the major factors that are responsible for lung cancer. Hence, the identification of novel compounds inhibiting TM and MMPs is the challenging task for the scientists. Even though synthetic drugs were developed, their toxicity and offtarget limit their usage. The current study aims to investigate the molecular simulations for bacterial derived stearic acid to estimate the in silico anticancer activity against TM and MMPs protein as target compounds and the findings were correlated with the standard drug vorinostat. Using Lamarckian genetic algorithm, the TM and MMPs were energy minimized and docked with stearic acid and vorinostat using auto dock 4.2 and visualized in PyMol software. Protein and ligand binding analysis revealed that stearic acid interacts with the amino acids of MMPs residues of PHE83, SER212, ALA213 and ASN214. It interacts with the TMs with two amino acid residues i.e. CYS407 and GLU408. Hence, compared to vorinostat, stearic acid shows a higher binding affinity towards MMPs and slightly lower affinity towards TM proteinase. We conclude that the computational analysis of ligand binding interaction of stearic acid suggests that it could be a potential inhibitor of matrix metallo proteinase and is effective against thrombomodulin and can be considered as an anticancer agent by in vivo studies.

scholarly journals Exploring the Conformational Dynamics of RNA Dependent RNA Polymerase of SARS-CoV-2 in the Presence of Various Nucleotide Analogues

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne V N ◽  
Uddhavesh Sonavane ◽  
Rajendra Joshi
Keyword(s):  
Rna Polymerase ◽  
Conformational Dynamics ◽  
Principal Component ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Strong Interactions ◽  
Binding Motif ◽  
Entry Site ◽  
Rna Dependent Rna Polymerase ◽  
Nucleotide Analogues

<p>RNA dependent RNA polymerase (RdRP) from positive stranded RNA viruses has always been a hot target for designing of new drugs as it is responsible for viral replication. The major class of drugs that are targeted against RdRP are nucleotide analogues. An extensive docking and molecular dynamics study describing the role of natural nucleotides (NTPs) and its analogues in imparting an inhibitory effect on the RdRP has been presented here. RdRP simulations in its apo, NTP-bound and analogue-bound form have been performed for a cumulative time of 1.9 μs. The conformational flexibility of the RdRP molecule was explored using Principal Component Analysis (PCA) and Markov State Modeling (MSM) Analysis. PCA inferred the presence of correlated motions along the conserved motifs of the RdRP. The ligand binding motif F and template binding motif G showed motions that are negatively correlated with one another. LYS 551, ARG 553 and ARG 555 which are a part of the motif F appear to form strong interactions with the ligand molecules. ARG 836, a primer binding residue was observed to strongly bind to the nucleotide analogues. The MSM analysis helped to observe different conformational states explored by the RdRP. The ensemble docking of the ligands on the Markov states suggested the involvement of the above residues in ligand interactions. The Markov states obtained clearly demarcated the open and closed conformations. The closed states were observed to have more favorable docking of the ligands. MSM analysis predicted a probable inhibitory mechanism involving the closing of the template entry site by reduction in the distance between the flanking finger and thumb subdomain. </p>

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

Remdesivir-Bound and Ligand-Free Simulations Reveal the Probable Mechanism of Inhibiting the RNA Dependent RNA Polymerase of SARS-CoV-2

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne V N ◽  
Uddhavesh Sonavane ◽  
Rajendra Joshi
Keyword(s):  
Rna Polymerase ◽  
Principal Component ◽  
Experimental Information ◽  
Strong Interactions ◽  
Entry Site ◽  
Rna Dependent Rna Polymerase ◽  
Gene Encoding ◽  
Strong Inhibitor ◽  
Ensemble Docking ◽  
Positive Strand Rna

<p>The efforts towards developing a potential drug against the current global pandemic, COVID-19, has increased in the past few months. Drug development strategies to target the RNA dependent RNA polymerase (RdRP) are being tried worldwide. The gene encoding this protein, is known to be conserved amongst positive strand RNA viruses. This enables an avenue to repurpose the drugs designed against earlier reported inhibitors of RdRP. One such strong inhibitor is remdesivir which has been used against EBOLA infections. The binding of remdesivir to RdRP of SARS-CoV-2 has been studied using the classical molecular dynamics and ensemble docking approach. A comparative study of the simulations of RdRP in the apo and remdesivir-bound form revealed blocking of the template entry site in the presence of remdesivir. The conformation changes leading to this event were captured through principal component analysis. The conformational and thermodynamic parameters supported the experimental information available on the involvement of crucial arginine, serine and aspartate residues belonging to the conserved motifs in RdRP functioning. The catalytic site comprising of SER 759, ASP 760, and ASP 761 (SDD) was observed to form strong contacts with remdesivir. The significantly strong interactions of these residues with remdesivir may infer the latter’s binding similar to the normal nucleotides thereby remaining unidentified by the exonuclease activity of RdRP. The ensemble docking of remdesivir too, comprehended the involvement of similar residues in interaction with the inhibitor. This information on crucial interactions between conserved residues of RdRP with remdesivir through <i>in-silico</i> approaches may be useful in designing inhibitors.<b></b></p>

Virtual Screening of the Indonesian Medicinal Plant and Zinc Databases for Potential Inhibitors of the RNA-Dependent RNA Polymerase (RdRp) of 2019 Novel Coronavirus

2020 ◽  
Vol 20 (6) ◽  
pp. 1430
Author(s):  
Muhammad Arba ◽  
Andry Nur-Hidayat ◽  
Ida Usman ◽  
Arry Yanuar ◽  
Setyanto Tri Wahyudi ◽  
...  
Keyword(s):  
Binding Energy ◽  
Rna Polymerase ◽  
Antiviral Drug ◽  
Dynamics Simulation ◽  
Human Beings ◽  
Rna Dependent Rna Polymerase ◽  
Energy Prediction ◽  
Binding Energy Prediction ◽  
Solvation Energies ◽  
Novel Coronavirus

The novel coronavirus disease 19 (Covid-19) which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a pandemic across the world, which necessitate the need for the antiviral drug discovery. One of the potential protein targets for coronavirus treatment is RNA-dependent RNA polymerase. It is the key enzyme in the viral replication machinery, and it does not exist in human beings, therefore its targeting has been considered as a strategic approach. Here we describe the identification of potential hits from Indonesian Herbal and ZINC databases. The pharmacophore modeling was employed followed by molecular docking and dynamics simulation for 40 ns. 151 and 14480 hit molecules were retrieved from Indonesian herbal and ZINC databases, respectively. Three hits that were selected based on the structural analysis were stable during 40 ns, while binding energy prediction further implied that ZINC1529045114, ZINC169730811, and 9-Ribosyl-trans-zeatin had tighter binding affinities compared to Remdesivir. The ZINC169730811 had the strongest affinity toward RdRp compared to the other two hits including Remdesivir and its binding was corroborated by electrostatic, van der Waals, and nonpolar contribution for solvation energies. The present study offers three hits showing tighter binding to RdRp based on MM-PBSA binding energy prediction for further experimental verification.

Potential Candidates against COVID-19 Targeting RNA-Dependent RNA Polymerase: A Comprehensive Review

2021 ◽  
Vol 22 ◽  
Author(s):  
Neetu Agrawal ◽  
Ahsas Goyal
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Host Cells ◽  
Rna Dependent Rna Polymerase ◽  
In Vivo Experiments ◽  
Contagious Nature ◽  
In Silico Studies ◽  
Viral Enzyme

: Due to the extremely contagious nature of SARS-COV-2, it presents a significant threat to humans worldwide. A plethora of studies are going on all over the world to discover the drug to fight SARS-COV-2. One of the most promising targets is RNA-dependent RNA polymerase (RdRp), responsible for viral RNA replication in host cells. Since RdRp is a viral enzyme with no host cell homologs, it allows the development of selective SARS-COV-2 RdRp inhibitors. A variety of studies used in silico approaches for virtual screening, molecular docking, and repurposing of already existing drugs and phytochemicals against SARS-COV-2 RdRp. This review focuses on collating compounds possessing the potential to inhibit SARS-COV-2 RdRp based on in silico studies to give medicinal chemists food for thought so that the existing drugs can be repurposed for the control and treatment of ongoing COVID-19 pandemic after performing in vitro and in vivo experiments.

Docking studies of tetra substituted pyrazolone derivatives as potential antiviral agents

2018 ◽  
Vol 5 (2) ◽  
pp. 5-8
Author(s):  
Jyothi Achuthanandhan ◽  
Baskar Lakshmanan
Keyword(s):  
Rna Polymerase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Antiviral Agents ◽  
Docking Studies ◽  
Binding Modes ◽  
Binding Interaction ◽  
Rna Dependent Rna Polymerase ◽  
Adme Prediction ◽  
Pyrazolone Derivatives

In an attempt to find potential antiviral agents, a series of pyrazolones (PA1-PA6& PC1-PC6) were designed and evaluated for their  DENVNS5 (RNA-dependent RNA polymerase) inhibitory activity. Molecular docking studies of all the designed compounds into the binding site of DENVNS5 (PDB Code: 4C11) were performed to gain a comprehensive understanding into rational binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue  PA6showed superior inhibitory activity against RNA dependent RNA polymerase. SAR  study indicated that the presence of an electron withdrawing substitution on pyrazolone derivatives significantly improves its binding interaction with the protein.Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness.

Sign in / Sign up

Export Citation Format

Share Document