Identification of therapeutic drugs against COVID-19 through computational investigation on drug repurposing and structural modification

Yun, Yangfang; Song, Heng-Yi; Ji, Yin; Huo, Da; Han, Feng; Li, Fēi; Jiang, Nan

doi:10.7555/jbr.34.20200044

Cited by 10 publications

(9 citation statements)

References 30 publications

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“…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. Interestingly, these drugs also seem to bind other crucial viral proteins, such as PLpro and Mpro/3CLpro [ 84 , 85 , 86 ], and to interfere in the interaction between the S protein and ACE2 receptor [ 82 , 83 ], suggesting multiple targets in the virus life cycle for these drugs.…”

Section: Discussionmentioning

confidence: 99%

“…In two studies, the spike/ACE2 interaction has been considered the target of simulated inhibition. MD and MDS analyses with 2080 FDA-approved molecules identified 238 compounds virtually binding the spike/ACE2 interaction interface, 10 of which were reported to have antiviral activity and with tenofovir and remdesivir showing the highest docking scores [ 82 ]. The authors found that remdesivir had stronger interactions with ACE2 than with spike, while TDF was closer to and interacted more strongly with the spike protein than the ACE2 receptor.…”

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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“…Several recent computational studies proposed that some potent molecules either directly bind to the interface, − to a distant site from the interface, or to the active site of ACE2 , with the goal of allosterically affecting the interactions between ACE2 and S1 and help prevent the viral entry of SARS-CoV-2. As mentioned earlier, DESRES also shared several MD simulations that were performed for ACE2 in complex with 78 compounds predicted to bind tightly to ACE2 .…”

Section: Resultsmentioning

confidence: 99%

Perturbation of ACE2 Structural Ensembles by SARS-CoV-2 Spike Protein Binding

Uyar

Dickson

2021

J. Chem. Theory Comput.

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The human ACE2 enzyme serves as a critical first recognition point of coronaviruses, including SARS-CoV-2. In particular, the extracellular domain of ACE2 interacts directly with the S1 tailspike protein of the SARS-CoV-2 virion through a broad protein–protein interface. Although this interaction has been characterized by X-ray crystallography, these structures do not reveal significant differences in the ACE2 structure upon S1 protein binding. In this work, using several all-atom molecular dynamics simulations, we show persistent differences in the ACE2 structure upon binding. These differences are determined with the linear discriminant analysis (LDA) machine learning method and validated using independent training and testing datasets, including long trajectories generated by D. E. Shaw Research on the Anton 2 supercomputer. In addition, long trajectories for 78 potent ACE2-binding compounds, also generated by D. E. Shaw Research, were projected onto the LDA classification vector in order to determine whether the ligand-bound ACE2 structures were compatible with S1 protein binding. This allows us to predict which compounds are “apo-like” versus “complex-like” and to pinpoint long-range ligand-induced allosteric changes in the ACE2 structure.

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“…The study conducted by salpini et al [45] on several permitted drugs and their metamorphosis effect on the binding affinity for the target enzyme has shown that medicines such as remdesivir display reduction in binding affinity against P323L metamorphosed RdRp; other medicines including tenofovir are found to be responsive against modified enzyme. Yun et al [46] have stated that tenofovir and remdesivir display utmost docking values.…”

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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Identification of therapeutic drugs against COVID-19 through computational investigation on drug repurposing and structural modification

Cited by 10 publications

References 30 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

Perturbation of ACE2 Structural Ensembles by SARS-CoV-2 Spike Protein Binding

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

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