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

<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>

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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

<p>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 <i>in silico</i> screening against two critical enzymes (3C-like protease (3CL<sup>pro</sup>) 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 3CL<sup>pro</sup>: 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.</p>

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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

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1802346 ◽

2020 ◽

pp. 1-20 ◽

Cited By ~ 2

Author(s):

Seref Gul ◽

Onur Ozcan ◽

Sinan Asar ◽

Alper Okyar ◽

Ibrahim Barıs ◽

...

Keyword(s):

Clinical Trials ◽

Rna Polymerase ◽

In Silico ◽

Viral Rna ◽

Rna Dependent Rna Polymerase ◽

Polymerase Inhibitors ◽

In Silico Identification ◽

Direct Use

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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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Repurposing Nonnucleoside Antivirals Against SARS-CoV2 NSP12 (RNA Dependent RNA Polymerase) and Identification of Domain Specific Interactions

10.26434/chemrxiv.12721634 ◽

2020 ◽

Author(s):

Feroza Begum ◽

UPASANA RAY

Keyword(s):

Rna Polymerase ◽

Particle Production ◽

Drug Repurposing ◽

Viral Rna ◽

Rna Dependent Rna Polymerase ◽

Domain Specific ◽

Virus Rna ◽

Promising Area ◽

Screening And Identification ◽

Approved Drugs

<p>The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp. We propose these three drugs as potential RdRp inhibitors based on the site of binding. </p>

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Repurposing Nonnucleoside Antivirals Against SARS-CoV2 NSP12 (RNA Dependent RNA Polymerase) and Identification of Domain Specific Interactions

10.26434/chemrxiv.12721634.v1 ◽

2020 ◽

Author(s):

Feroza Begum ◽

UPASANA RAY

Keyword(s):

Rna Polymerase ◽

Particle Production ◽

Drug Repurposing ◽

Viral Rna ◽

Rna Dependent Rna Polymerase ◽

Domain Specific ◽

Virus Rna ◽

Promising Area ◽

Screening And Identification ◽

Approved Drugs

<p>The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp. We propose these three drugs as potential RdRp inhibitors based on the site of binding. </p>

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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.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Seref Gul ◽

Onur Ozcan ◽

sinan asar ◽

Alper Okyar ◽

Ibrahim Barıs ◽

...

Keyword(s):

Rna Polymerase ◽

Binding Sites ◽

Cost Effective ◽

Rna Dependent Rna Polymerase ◽

High Affinity ◽

In Silico Identification ◽

Approved Drugs ◽

Dynamics Simulations ◽

Fda Approved Drugs ◽

High Binding Affinity

<div>We performed repurposing of FDA approved drugs against SARS-CoV-2 3 chymotrypsin like protease and RNA-dependent RNA polymerase. During the screening, 3948 drugs approved by the U.S. Food and Drug Administration (FDA) to target the active site of 3CLpro and nsp8 binding sites of RdRp and, in turn, disturb SARS-CoV-2 life cycle in host cell. As a result of molecular docking and molecular</div><div>dynamics simulations, several drugs with high binding affinity to both SARS-Cov-2 3CLpro and RdRp targets were identified. While drugs such as tetracycline and its derivatives, dihydroergotamine, ergotamine, dutasteride, nelfinavir, paliperidone, and conivaptan were identified to bind SARS-Cov-2 3CLpro; tipranavir, nelfinavir, dihydroergotamine, conivaptan, dutasterid and eltrombopag were found to bind nsp8 binding site of RdRp. Notably, further analysis of the results showed that ergotamine,</div><div>dihydroergotamine, 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 tetracycline and its derivatives, dutasteride, ergotamine, bromocriptine, tipranavir, conivaptan, paliperidone, eltrombopag drugs have the potential to be used alone or in combination as adjuvant for</div><div>the treatment of SARS-CoV-2 infected patients.</div>

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Combining SARS-CoV-2 Proofreading Exonuclease and RNA-Dependent RNA Polymerase Inhibitors as a Strategy to Combat COVID-19: A High-Throughput in silico Screening

Frontiers in Microbiology ◽

10.3389/fmicb.2021.647693 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shradha Khater ◽

Pawan Kumar ◽

Nandini Dasgupta ◽

Gautam Das ◽

Shashikant Ray ◽

...

Keyword(s):

Rna Polymerase ◽

Binding Free Energy ◽

Solvent Accessibility ◽

Nucleoside Analogs ◽

Md Simulations ◽

Rna Dependent Rna Polymerase ◽

Born Model ◽

Docking Approach ◽

Approved Drugs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide. Currently, many clinical trials in search of effective COVID-19 drugs are underway. Viral RNA-dependent RNA polymerase (RdRp) remains the target of choice for prophylactic or curative treatment of COVID-19. Nucleoside analogs are the most promising RdRp inhibitors and have shown effectiveness in vitro, as well as in clinical settings. One limitation of such RdRp inhibitors is the removal of incorporated nucleoside analogs by SARS-CoV-2 exonuclease (ExoN). Thus, ExoN proofreading activity accomplishes resistance to many of the RdRp inhibitors. We hypothesize that in the absence of highly efficient antivirals to treat COVID-19, combinatorial drug therapy with RdRp and ExoN inhibitors will be a promising strategy to combat the disease. To repurpose drugs for COVID-19 treatment, 10,397 conformers of 2,240 approved drugs were screened against the ExoN domain of nsp14 using AutoDock VINA. The molecular docking approach and detailed study of interactions helped us to identify dexamethasone metasulfobenzoate, conivaptan, hesperidin, and glycyrrhizic acid as potential inhibitors of ExoN activity. The results were further confirmed using molecular dynamics (MD) simulations and molecular mechanics combined with generalized Born model and solvent accessibility method (MM-GBSA) calculations. Furthermore, the binding free energy of conivaptan and hesperidin, estimated using MM-GBSA, was −85.86 ± 0.68 and 119.07 ± 0.69 kcal/mol, respectively. Based on docking, MD simulations and known antiviral activities, and conivaptan and hesperidin were identified as potential SARS-CoV-2 ExoN inhibitors. We recommend further investigation of this combinational therapy using RdRp inhibitors with a repurposed ExoN inhibitor as a potential COVID-19 treatment.

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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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