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

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.

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

Journal of Medical Microbiology ◽

10.1099/jmm.0.001203 ◽

2020 ◽

Vol 69 (6) ◽

pp. 864-873 ◽

Cited By ~ 6

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.

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

10.26434/chemrxiv.12200495 ◽

2020 ◽

Cited By ~ 1

Author(s):

Trinath Chowdhury ◽

Gourisankar Roymahapatra ◽

Santi M Mandal

Keyword(s):

Rna Polymerase ◽

Active Site ◽

In Silico ◽

Significant Interaction ◽

Rna Dependent Rna Polymerase ◽

Docking Analysis ◽

Replicase Protein ◽

Arsenical Compounds ◽

Viral Replicase ◽

In Silico Identification

The work demonstrate screening of several arsenical compounds against RdRp of coronavirus. The study implies out of all arsenical compounds, darinaparsin shows its most effective results based on in silico docking analysis. This study also confirmed the significant interaction between the active site of viral replicase protein, endoribonuclease protein and different proteases with darinaparsin.

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

10.26434/chemrxiv.12200495.v1 ◽

2020 ◽

Author(s):

Trinath Chowdhury ◽

Gourisankar Roymahapatra ◽

Santi M Mandal

Keyword(s):

Rna Polymerase ◽

Active Site ◽

In Silico ◽

Significant Interaction ◽

Rna Dependent Rna Polymerase ◽

Docking Analysis ◽

Replicase Protein ◽

Arsenical Compounds ◽

Viral Replicase ◽

In Silico Identification

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Natural plant products as potential inhibitors of RNA dependent RNA polymerase of Severe Acute Respiratory Syndrome Coronavirus-2

PLoS ONE ◽

10.1371/journal.pone.0251801 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251801

Author(s):

Shruti Koulgi ◽

Vinod Jani ◽

Mallikarjunachari Uppuladinne V. N. ◽

Uddhavesh Sonavane ◽

Rajendra Joshi

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Rna Polymerase ◽

Conformational Changes ◽

Drug Repurposing ◽

Principal Component ◽

Salt Bridge ◽

Potential Effect ◽

Tinospora Cordifolia ◽

Rna Dependent Rna Polymerase ◽

Dynamics Simulations

Drug repurposing studies targeting inhibition of RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have exhibited the potential effect of small molecules. In the present work a detailed interaction study between the phytochemicals from Indian medicinal plants and the RdRP of SARS-CoV-2 has been performed. The top four phytochemicals obtained through molecular docking were, swertiapuniside, cordifolide A, sitoindoside IX, and amarogentin belonging to Swertia chirayita, Tinospora cordifolia and Withania somnifera. These ligands bound to the RdRP were further studied using molecular dynamics simulations. The principal component analysis of these systems showed significant conformational changes in the finger and thumb subdomain of the RdRP. Hydrogen bonding, salt-bridge and water mediated interactions supported by MM-GBSA free energy of binding revealed strong binding of cordifolide A and sitoindoside IX to RdRP. The ligand-interacting residues belonged to either of the seven conserved motifs of the RdRP. These residues were polar and charged amino acids, namely, ARG 553, ARG 555, ASP 618, ASP 760, ASP 761, GLU 811, and SER 814. The glycosidic moieties of the phytochemicals were observed to form favourable interactions with these residues. Hence, these phytochemicals may hold the potential to act as RdRP inhibitors owing to their stability in binding to the druggable site.

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In Silico Identification of Widely Used and Well Tolerated Drugs That May Inhibit SARSCov- 2 3C-like Protease and Viral RNA-Dependent RNA Polymerase Activities, and May Have Potential to Be Directly Used in Clinical Trials

10.26434/chemrxiv.12123204.v2 ◽

2020 ◽

Author(s):

Seref Gul ◽

Onur Ozcan ◽

sinan asar ◽

Alper Okyar ◽

Ibrahim Barıs ◽

...

Keyword(s):

Rna Polymerase ◽

In Silico ◽

Cost Effective ◽

Viral Rna ◽

Rna Dependent Rna Polymerase ◽

Docking Simulations ◽

High Binding ◽

Approved Drugs ◽

Dynamics Simulations ◽

Fda Approved Drugs

Despite drastic strict measures, the spread of the SARS-CoV-2 is ongoing all around the world. There is no vaccine developed against this virus and no approved medication to be used for the treatment of COVID-2019. In this study, we performed in silico screening against two critical enzymes (3C-like protease (3CLpro) and viral RNA-dependent RNA polymerase (RdRp)), which play important roles in the SARS-CoV-2 life cycle, by using the U.S. Food and Drug Administration (FDA) approved drugs. Our docking simulations enable us to identify several hundred drugs that have high binding affinity for each target. To evaluate persistence of the drugs’ binding to each target near to physiological conditions we selected well tolerated and widely used ones for the molecular dynamics simulations. Simulations results revealed that following drugs were stably interacting with SARS-Cov-2 3CLpro: tetracycline and its derivatives, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone. A similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan were bound with the enzyme during the simulation with high binding energy. Detailed analysis of docking results suggested that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. Since these drugs are well tolerated, cost effective and widely used, our study suggested that they have potential to be used in clinical trial for the treatment of SARS-CoV-2 infected patients.

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Bioactive Molecules of Tea as Potential Inhibitors for RNA-Dependent RNA Polymerase of SARS-CoV-2

Frontiers in Medicine ◽

10.3389/fmed.2021.684020 ◽

2021 ◽

Vol 8 ◽

Author(s):

Vijay Kumar Bhardwaj ◽

Rahul Singh ◽

Jatin Sharma ◽

Vidya Rajendran ◽

Rituraj Purohit ◽

...

Keyword(s):

Rna Polymerase ◽

Drug Repurposing ◽

Docking Studies ◽

Antiviral Drugs ◽

Bioactive Molecules ◽

Rna Dependent Rna Polymerase ◽

Dynamics Simulations ◽

Potential Inhibitors

The coronavirus disease (COVID-19), a worldwide pandemic, is caused by the severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). At this moment in time, there are no specific therapeutics available to combat COVID-19. Drug repurposing and identification of naturally available bioactive molecules to target SARS-CoV-2 are among the key strategies to tackle the notorious virus. The enzyme RNA-dependent RNA polymerase (RdRp) performs a pivotal role in replicating the virus. RdRp is a prime target for Remdesivir and other nucleotides analog-based antiviral drugs. In this study, we showed three bioactive molecules from tea (epicatechin-3,5-di-O-gallate, epigallocatechin-3,5-di-O-gallate, and epigallocatechin-3,4-di-O-gallate) that showed better interaction with critical residues present at the catalytic center and the NTP entry channel of RdRp than antiviral drugs Remdesivir and Favipiravir. Our computational approach to identify these molecules included molecular docking studies, followed by robust molecular dynamics simulations. All the three molecules are readily available in tea and could be made accessible along with other medications to treat COVID-19 patients. However, these results require validation by further in vitro and in vivo studies.

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Drug repurposing using similarity-based target prediction, docking studies and scaffold hopping of lefamulin

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201201113712 ◽

2020 ◽

Vol 17 ◽

Author(s):

Shikha Sharma ◽

Shweta Sharma ◽

Vaishali Pathak ◽

Parwinder Kaur ◽

Rajesh Kumar Singh

Keyword(s):

In Silico ◽

Target Prediction ◽

Drug Repurposing ◽

Docking Studies ◽

Target Protein ◽

Future Perspective ◽

Antibacterial Drug ◽

Scaffold Hopping ◽

Target Proteins ◽

Renin Inhibitors

Aim: To investigate and validate the potential target proteins for drug repurposing of newly FDA approved antibacterial drug. Background: Drug repurposing is the process of assigning indications for drugs other than the one(s) that they were initially developed for. Discovery of entirely new indications from already approved drugs is highly lucrative as it minimizes the pipeline of the drug development process by reducing time and cost. In silico driven technologies made it possible to analyze molecules for different target proteins which are not yet explored. Objective: To analyze possible targets proteins for drug repurposing of lefamulin and their validation. Also, in silico prediction of novel scaffolds from lefamulin has been performed for assisting medicinal chemists in future drug design. Methods: A similarity-based prediction tool was employed for predicting target protein and further investigated using docking studies on PDB ID: 2V16. Besides, various in silico tools were employed for prediction of novel scaffolds from lefamulin using scaffold hopping technique followed by evaluation with various in silico parameters viz., ADME, synthetic accessibility and PAINS. Results: Based on the similarity and target prediction studies, renin is found as the most probable target protein for lefamulin. Further, validation studies using docking of lefamulin revealed the significant interactions of lefamulin with the binding pocket of the target protein. Also, three novel scaffolds were predicted using scaffold hopping technique and found to be in the limit to reduce the chances of drug failure in the physiological system during the last stage approval process. Conclusion: To encapsulate the future perspective, lefamulin may assist in the development of the renin inhibitors and, also three possible novel scaffolds with good pharmacokinetic profile can be developed into both as renin inhibitors and for bacterial infections.

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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

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200727153643 ◽

2020 ◽

Vol 20 ◽

Cited By ~ 1

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.

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