Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Fadaka, Adewale Oluwaseun; Aruleba, Raphael Taiwo; Sibuyi, Nicole Remaliah Samantha; Klein, Ashwil; Madiehe, Abram Madimabe; Meyer, Mervin

doi:10.1080/07391102.2020.1847197

Cited by 31 publications

(21 citation statements)

References 60 publications

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“…In concordance with these conclusions, a recent review on the effect of ANNAs on the SARS-CoV-2 RdRp arrived at the same prediction for Lamivudine ( 84 ). Additionally, a recent docking report indicates the putative binding of Lamivudine to the main protease (MPro) of the SARS-CoV-2 ( 35 ), therefore it seems possible that, as reviewed here, Lamivudine could inhibit the three key SARS-CoV-2 processes: Spike/ACE2 interaction, processing by MPro and, as found here, RNA replication by the SARS-CoV-2 RdRp polymerase.…”

Section: Other Repurposing or Putative Reusage Of Annas And Lamivudine Against Sars-cov-2 And Covid-19supporting

confidence: 55%

“…Many, if not all of them interact with their target enzymes and also with other nucleotide-binding proteins, This lack of specificity opens the door to repurposing ANNAs for other therapeutic purposes. In addition to the functional triphosphate form of ANNAs, studies of drug repurposing have predicted that ANNAs and other drugs may bind to surface viral proteins and could interfere with viral entrance through the cell membranes ( 33 – 35 ). In summary, the lack of total specificity of these nucleoside/nucleotide analogues is the source of the heterogeneous effects that might allow the repurposing of these drugs and their pro-drugs in other viral illnesses and oncogenic processes.…”

Section: Common and Distinctive Features On The Mechanism Of Action Of Antiviral Nucleoside/nucleotide Analoguesmentioning

confidence: 99%

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Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

2021

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Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

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Section: Other Repurposing or Putative Reusage Of Annas And Lamivudine Against Sars-cov-2 And Covid-19supporting

confidence: 55%

Section: Common and Distinctive Features On The Mechanism Of Action Of Antiviral Nucleoside/nucleotide Analoguesmentioning

confidence: 99%

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

2021

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“…The interactions between an antigenic molecules and an immune receptors molecules are crucial to effectively transport the antigenic molecule and to activate immune response 54 , 55 . Therefore, docking analysis was carried out between the immune receptor molecules (MCHs and TLRs) and the designed vaccines (DV-1–4) in order to investigate possible interactions, binding energy and poses.…”

Section: Resultsmentioning

confidence: 99%

Immunoinformatics design of a novel epitope-based vaccine candidate against dengue virus

Fadaka

Sibuyi

Martin

et al. 2021

Sci Rep

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Dengue poses a global health threat, which will persist without therapeutic intervention. Immunity induced by exposure to one serotype does not confer long-term protection against secondary infection with other serotypes and is potentially capable of enhancing this infection. Although vaccination is believed to induce durable and protective responses against all the dengue virus (DENV) serotypes in order to reduce the burden posed by this virus, the development of a safe and efficacious vaccine remains a challenge. Immunoinformatics and computational vaccinology have been utilized in studies of infectious diseases to provide insight into the host–pathogen interactions thus justifying their use in vaccine development. Since vaccination is the best bet to reduce the burden posed by DENV, this study is aimed at developing a multi-epitope based vaccines for dengue control. Combined approaches of reverse vaccinology and immunoinformatics were utilized to design multi-epitope based vaccine from the sequence of DENV. Specifically, BCPreds and IEDB servers were used to predict the B-cell and T-cell epitopes, respectively. Molecular docking was carried out using Schrödinger, PATCHDOCK and FIREDOCK. Codon optimization and in silico cloning were done using JCAT and SnapGene respectively. Finally, the efficiency and stability of the designed vaccines were assessed by an in silico immune simulation and molecular dynamic simulation, respectively. The predicted epitopes were prioritized using in-house criteria. Four candidate vaccines (DV-1–4) were designed using suitable adjuvant and linkers in addition to the shortlisted epitopes. The binding interactions of these vaccines against the receptors TLR-2, TLR-4, MHC-1 and MHC-2 show that these candidate vaccines perfectly fit into the binding domains of the receptors. In addition, DV-1 has a better binding energies of − 60.07, − 63.40, − 69.89 kcal/mol against MHC-1, TLR-2, and TLR-4, with respect to the other vaccines. All the designed vaccines were highly antigenic, soluble, non-allergenic, non-toxic, flexible, and topologically assessable. The immune simulation analysis showed that DV-1 may elicit specific immune response against dengue virus. Moreover, codon optimization and in silico cloning validated the expressions of all the designed vaccines in E. coli. Finally, the molecular dynamic study shows that DV-1 is stable with minimum RMSF against TLR4. Immunoinformatics tools are now applied to screen genomes of interest for possible vaccine target. The designed vaccine candidates may be further experimentally investigated as potential vaccines capable of providing definitive preventive measure against dengue virus infection.

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“…The pharmacokinetics and toxicological properties of the ligands (Tables 1 and 2) were analyzed according to previous methods to investigate how molecules can access the target site of M pro after entering the bloodstream. This analysis is also crucial for analyzing the efficacy of molecules [42,43]. All parameters were within the ROF cut-off range for the test compounds and present no bystander toxicity effects since toxicity is the main task in developing new medications.…”

Section: Adme/tox Predictionmentioning

confidence: 99%

Development of Effective Therapeutic Molecule from Natural Sources against Coronavirus Protease

Fadaka

Sibuyi

Martin

et al. 2021

IJMS

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The SARS-CoV-2 main protease (Mpro) is one of the molecular targets for drug design. Effective vaccines have been identified as a long-term solution but the rate at which they are being administered is slow in several countries, and mutations of SARS-CoV-2 could render them less effective. Moreover, remdesivir seems to work only with some types of COVID-19 patients. Hence, the continuous investigation of new treatments for this disease is pivotal. This study investigated the inhibitory role of natural products against SARS-CoV-2 Mpro as repurposable agents in the treatment of coronavirus disease 2019 (COVID-19). Through in silico approach, selected flavonoids were docked into the active site of Mpro. The free energies of the ligands complexed with Mpro were computationally estimated using the molecular mechanics-generalized Born surface area (MM/GBSA) method. In addition, the inhibition process of SARS-CoV-2 Mpro with these ligands was simulated at 100 ns in order to uncover the dynamic behavior and complex stability. The docking results showed that the selected flavonoids exhibited good poses in the binding domain of Mpro. The amino acid residues involved in the binding of the selected ligands correlated well with the residues involved with the mechanism-based inhibitor (N3) and the docking score of Quercetin-3-O-Neohesperidoside (−16.8 Kcal/mol) ranked efficiently with this inhibitor (−16.5 Kcal/mol). In addition, single-structure MM/GBSA rescoring method showed that Quercetin-3-O-Neohesperidoside (−87.60 Kcal/mol) is more energetically favored than N3 (−80.88 Kcal/mol) and other ligands (Myricetin 3-Rutinoside (−87.50 Kcal/mol), Quercetin 3-Rhamnoside (−80.17 Kcal/mol), Rutin (−58.98 Kcal/mol), and Myricitrin (−49.22 Kcal/mol). The molecular dynamics simulation (MDs) pinpointed the stability of these complexes over the course of 100 ns with reduced RMSD and RMSF. Based on the docking results and energy calculation, together with the RMSD of 1.98 ± 0.19 Å and RMSF of 1.00 ± 0.51 Å, Quercetin-3-O-Neohesperidoside is a better inhibitor of Mpro compared to N3 and other selected ligands and can be repurposed as a drug candidate for the treatment of COVID-19. In addition, this study demonstrated that in silico docking, free energy calculations, and MDs, respectively, are applicable to estimating the interaction, energetics, and dynamic behavior of molecular targets by natural products and can be used to direct the development of novel target function modulators.

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Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

Cited by 31 publications

References 60 publications

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

Immunoinformatics design of a novel epitope-based vaccine candidate against dengue virus

Development of Effective Therapeutic Molecule from Natural Sources against Coronavirus Protease

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