Evaluation of drug repositioning by molecular docking of pharmaceutical resources available in the Brazilian healthcare system against SARS-CoV-2

Grahl, Matheus V. Coste; Alcará, Allan Marinho; Perin, Ana Paula; Moro, Carlo Frederico; Pinto, Éderson Sales Moreira; Feltes, Bruno César; Ghilardi, Isadora; Rodrigues, Fernanda Silva; Dorn, Márcio; Costa, Jaderson Costa da; Souza, Osmar Norberto de; Ligabue-Braun, Rodrigo

doi:10.1016/j.imu.2021.100539

Cited by 17 publications

(11 citation statements)

References 69 publications

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“…As reviewed in this work, several in silico studies suggest the inhibitory activity of tenofovir and its derivative prodrugs TDF and TAF on their presumed and more obvious viral target, the SARS-CoV-2 RdRp protein, likely competing with the natural nucleotide adenosine for the enzyme binding and then acting as chain terminators [ 50 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Notably, in one of these studies [ 81 ] a better binding activity of tenofovir with the P323L mutated RdRp protein was observed in comparison with remdesivir, further suggesting tenofovir use in COVID-19 treatment.…”

Section: Discussionmentioning

confidence: 99%

“…This value was not so different from those of the four natural nucleotide triphosphates (NTPs), suggesting that this drug may efficiently compete with natural NTPs for the binding site of SARS-CoV-2 RdRp, then possibly inhibiting the enzyme. To increase the degree of reliability of MD, Grahl and colleagues [ 77 ] used three different docking software to virtually screen 48 antiviral drugs against different SARS-CoV-2 proteins (S protein in different conformation states, its isolated receptor binding domain, Mpro/3CLpro, RdRp, nsp10 and nsp16). Combining data derived from the three analyses by considering both lipophilic and hydrophilic matches, the authors selected 18 protein-ligand complexes for further stability and binding strength analysis.…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

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Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Section: Pre-clinical Studiesmentioning

confidence: 99%

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

et al. 2021

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“…We quantified the accuracy of the system by screening known viral anti-polymerase drugs such as rhoifolin, penciclovir, ribavirin, dasabuvir, and cytidine-5’-triphosphate, as effective inhibitors of SARS-CoV-2 RdRp activity. Among them, rhoifolin, a flavonoid earlier shown to inhibit SARS-CoV 3CL Pro (21) and penciclovir, a guanosine analogue that is predicted to bind to SARS-CoV-2 RdRp via molecular docking studies (22), did not significantly inhibit SARS-CoV-2 RdRp activity. Ribavirin, a broad-spectrum antiviral prevents viral RNA synthesis by depleting cellular guanosine triphosphate (22).…”

Section: Discussionmentioning

confidence: 99%

“…Among them, rhoifolin, a flavonoid earlier shown to inhibit SARS-CoV 3CL Pro (21) and penciclovir, a guanosine analogue that is predicted to bind to SARS-CoV-2 RdRp via molecular docking studies (22), did not significantly inhibit SARS-CoV-2 RdRp activity. Ribavirin, a broad-spectrum antiviral prevents viral RNA synthesis by depleting cellular guanosine triphosphate (22). The incorporation of ribavirin triphosphate by RdRp has been shown to result in lethal viral mutagenesis (23, 24).…”

Section: Discussionmentioning

confidence: 99%

Screening of SARS-CoV-2 Antivirals Through a Cell-Based RNA-Dependent RNA Polymerase (RdRp) Reporter Assay

Uppal

Tuffo

Khaiboullina

et al. 2022

Preprint

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COVID-19 (Coronavirus Disease 2019) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus-2) continues to pose international public health threat and thus far, has resulted in greater than 5.6 million deaths worldwide. Vaccines are critical tools to limit COVID-19 spread, but antiviral drug development is an ongoing global priority due to fast spreading COVID-19 variants that may elude vaccines efficacies. The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is an essential enzyme of viral replication and transcription machinery complex. Therefore, the RdRp is an attractive target for the development of effective anti-COVID-19 therapeutics. In this study, we developed a cell-based assay to determine the enzymatic activity of SARS-CoV-2 RdRp through luciferase reporter system. The SARS-CoV-2 RdRp reporter assay was validated using a known inhibitors of RdRp polymerase, remdesivir along with other anti-virals including ribavirin, penciclovir, rhoifolin, 5’CT, and dasabuvir. Among these inhibitors, dasabuvir (FDA-approved drug) exhibited promising RdRp inhibitory activity. Anti-viral activity of dasabuvir was also tested on the replication of SARS-CoV-2 through infection of Vero E6 cells. Dasabuvir inhibited the replication of SARS-CoV-2, USA-WA1/2020 as well as B.1.617.2 (delta variant) in Vero E6 cells in a dose-dependent manner with IC50 values 9.47 μM and 10.48 μM, for USA-WA1/2020 and B.1.617.2 variants, respectively). Our results suggests that dasabuvir can be further evaluated as a therapeutic drug for COVID-19. In addition, our assays provide robust, target-specific, and high-throughput screening compatible (z- and z’-factors of > 0.5) platforms that will be a valuable tool for the screening SARS-CoV-2 RdRp inhibitors.SignificanceSARS-CoV-2 has caused a major public crisis world has seen in recent history. Development of vaccines and emergency use authorization of anti-virals are helping in reducing the burden of SARS-CoV-2 caused hospitalization and deaths. However, there is still need for optimal anti-viral(s) that can efficiently block viral propagation, and targeting viral polymerase (RdRp) is an among the most suitable targets for clamping viral replication. In this study, we developed a cell-based assay to screen potential compounds capable of blocking RdRp activity. The efficacy of our assay was validated by using already approved anti-virals, which reduced RdRp activity and slowed the replication of two SARS-CoV-2 variants (WA1 USA-WA1/2020 and B.1.617.2) in a cell culture model. This confirmed that our system can be used for identifying potential anti-SARS-CoV-2 anti-virals.

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“…In addition, the docking calculations were performed following the recommendations of the sampling region of the tests experimentally ( Zhao et al, 2021 ). Predictions of the relative covalent and non-covalent binding energies were made from the sampling algorithm and scoring function offered by AutoDock, and using Molegro Molecular predictions, in order to calculate the contributions of the molecular interactions offered by the tool, such as hydrogen bonds, hydrophobic bonds, electrostatic bonds, and also covalent bonds at the binding site as suggested ( Grahl et al, 2021 , Grau-Expósito et al, 2022 ) (see Supplementary material - Table S1). In addition, the non-covalent union was compared with the covalent one after the construction of the covalent model as suggested ( Macchiagodena et al, 2022 ).…”

Section: Methodological Detailsmentioning

confidence: 99%

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

Alvarado

Olivarez

Lossada

et al. 2022

Computational Biology and Chemistry

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Evaluation of drug repositioning by molecular docking of pharmaceutical resources available in the Brazilian healthcare system against SARS-CoV-2

Cited by 17 publications

References 69 publications

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Screening of SARS-CoV-2 Antivirals Through a Cell-Based RNA-Dependent RNA Polymerase (RdRp) Reporter Assay

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

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