Structural analogues of existing anti-viral drugs inhibit SARS-CoV-2 RNA dependent RNA polymerase: A computational hierarchical investigation

Hasan, Md. Kamrul; Kamruzzaman, Mohammad; Manjur, Omar Hamza Bin; Mahmud, Araf; Hussain, Nazmul; Mondal, Muhammad Shafiul Alam; Hosen, Md. Ismail; Bello, Martiniano; Rahman, Atiqur

doi:10.1016/j.heliyon.2021.e06435

Cited by 12 publications

(7 citation statements)

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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%

“…Interestingly, they found that tenofovir in its active triphosphate form, although it had docking score lower than other nucleoside/nucleotide analog reverse-transcriptase inhibitors (NRTIs) like abacavir (ABC), FTC and zidovudine (ZDV), showed more stable binding over time with the RdRp catalytic site, and was the only one to directly interact and bind with the residue D760 within the nucleotide binding site of the enzyme, suggesting that this NRTI could be an important drug candidate against SARS-Cov-2 infection. Using a similar approach, Hasan et al [ 79 ] screened a library of 2400 compounds comprising approved RdRp inhibitor drugs, including tenofovir, and their structural analogues, in order to identify new potential inhibitors of the viral enzyme. The authors performed an initial virtual screening and validated the results by MD, using a semi-flexible docking approach, to identify the best compounds.…”

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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“…Furthermore, study conducted on the binding affinity of numerous systems to diverse dynamic states of RdRp protein, using a molecular dynamics simulation approach, have revealed that tenofovir shows good binding energy value and it has equivalent value with respect to the four natural nucleotide triphosphates (NTPs). This signifies that it may be potential drug in the race with natural NTPs aimed at binding place of SARS-CoV-2 proteins [43]. Hasan et al [44] extensively investigated a number of systems including various permitted RdRp inhibitor medicines, containing tenofovir and their structural correspondents, to search for a new probable inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Computational study of some potential inhibitors of COVID‐19: A DFT analysis

2022

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Background: There is an urgent demand of drug or therapy to control the COVID-19. Until July 22, 2021 the worldwide total number of cases reported is more than 192 million and the total number of deaths reported is more than 4.12 million. Several countries have given emergency permission for use of repurposed drugs for the treatment of COVID-19 patients. This report presents a computational analysis on repurposing drugs-tenofovir, bepotastine, epirubicin, epoprostenol, tirazavirin, aprepitant and valrubicin, which can be potential inhibitors of the COVID-19. Method: Density functional theory (DFT) technique is applied for computation of these repurposed drug. For geometry optimization, functional B3LYP/6-311G (d, p) is selected within DFT framework. Results: DFT based descriptors -highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap, molecular hardness, softness, electronegativity, electrophilicity index, nucleophilicity index and dipole moment of these species are computed. IR and Raman activities are also analysed and studied. The result shows that the HOMO-LUMO gap of these species varies from 1.061 eV to 5.327 eV. Compound aprepitant with a HOMO-LUMO gap of 1.419 eV shows the maximum intensity of IR (786.176 km mol -1 ) and Raman spectra (15036.702 a.u.). Conclusion: Some potential inhibitors of COVID-19 are studied by using DFT technique. This study shows that epirubicin is the most reactive compound whereas tenofovir is found to be the most stable. Further analysis and clinical trials of these compounds will provide more insight.

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“…Molecular docking, MD simulations, and MM/GBSA approaches have also been used to examine the role of several short ionic peptides in inhibiting RdRp . Other similar studies include refs − .…”

Section: Methods and Approachesmentioning

confidence: 99%

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Gao¹,

Wang²,

Chen³

et al. 2022

Chem. Rev.

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Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus–host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component in combating coronavirus disease 2019 (COVID-19) due to their low cost, their efficiency, and the fact that they are free from safety and ethical constraints. Additionally, the mechanism that governs the global evolution and transmission of SARS-CoV-2 cannot be revealed from individual experiments and was discovered by integrating genotyping of massive viral sequences, biophysical modeling of protein–protein interactions, deep mutational data, deep learning, and advanced mathematics. There exists a tsunami of literature on the molecular modeling, simulations, and predictions of SARS-CoV-2 and related developments of drugs, vaccines, antibodies, and diagnostics. To provide readers with a quick update about this literature, we present a comprehensive and systematic methodology-centered review. Aspects such as molecular biophysics, bioinformatics, cheminformatics, machine learning, and mathematics are discussed. This review will be beneficial to researchers who are looking for ways to contribute to SARS-CoV-2 studies and those who are interested in the status of the field.

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Structural analogues of existing anti-viral drugs inhibit SARS-CoV-2 RNA dependent RNA polymerase: A computational hierarchical investigation

Cited by 12 publications

References 59 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

Computational study of some potential inhibitors of COVID‐19: A DFT analysis

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

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