Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach

Gangadharan, Sivakumar; Ambrose, Jenifer Mallavarpu; Rajajagadeesan, Anusha; Kullappan, Malathi; Patil, Shankargouda; Gandhamaneni, Sri Harshini; Veeraraghavan, Vishnu Priya; Nakkella, Aruna Kumari; Agarwal, Ambuj Kumar; Jayaraman, Selvaraj; Mohan, Surapaneni Krishna

doi:10.1016/j.jiph.2022.09.007

Cited by 12 publications

(7 citation statements)

References 65 publications

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“…One of these, known as Nsp12 or RNA-dependent RNA polymerase (RdRp), catalyzes the synthesis of viral RNA and plays a central role in the replication and transcription cycle of SARS-CoV-2 with Nsp7 and Nsp8 as co-factors [31,32]. Therefore, Nsp12 is considered a primary target for antiviral agents, with the potential for treating COVID-19 [33], and possibly other coronaviral diseases because it is a highly conserved motif. For example, sequence alignment results from the literature shows 96% common identity between SARS-CoV and SARS-CoV-2 [34].…”

Section: Virological Contextmentioning

confidence: 99%

See 1 more Smart Citation

On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation

Mohammed,

Chougule,

Ala

et al. 2024

Preprint

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The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. We have now investigated all bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies with minodronate could be valuable.

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Section: Virological Contextmentioning

confidence: 99%

“…Few studies also reported the screening of analogues of different scaffolds such as quinolines [47], cytidines [52] and andrographolides [53]. It's also common for repurposing efforts to propose drugs that are yet to be tested in vitro [27,33,[45][46][47][54][55][56][57][58][59][60].…”

Section: Medicinal Chemistry Contextmentioning

confidence: 99%

On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation

Mohammed,

Chougule,

Ala

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Remdesivir, a nucleotide analog prodrug, has been shown to have broad-spectrum antiviral activity against SARS-CoV-2 [81][82][83]. In silico studies have demonstrated that Remdesivir can inhibit the RNA polymerase of SARS-CoV-2, thereby preventing viral replication [81,84]. Furthermore, Favipiravir, another nucleotide analog, has also shown promising results in in silico studies.…”

Section: Therapeutic Interventions Using In Silico Analysis Of Drug C...mentioning

confidence: 99%

Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

Mushebenge,

Ugbaja,

Mbatha

et al. 2023

IJMS

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The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, and transmembrane protease serine 2 (TMPRSS2). In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat Mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of the drug candidates to target receptors, providing insight into their potential efficacy. This study is aimed at assessing the useful contributions of the application of computational instruments in the discovery of receptors targeted in SARS-CoV-2. It further highlights some identified advantages and limitations of these studies, thereby revealing some complementary experimental validation to ensure the efficacy and safety of identified drug candidates.

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“…One of these, known as Nsp12 or RNA-dependent RNA polymerase (RdRp), catalyzes the synthesis of viral RNA and plays a central role in the replication and transcription cycle of SARS-CoV-2 with Nsp7 and Nsp8 as co-factors [8,9]. Therefore, Nsp12 is considered a primary target for antiviral agents, with the potential for treating COVID-19 [10], and possibly other coronaviral diseases because it is a highly conserved motif. For example, sequence alignment results from the literature shows 96% common identity between SARS-CoV and SARS-CoV-2 [11].…”

Section: Introductionmentioning

confidence: 99%

“…Few studies also reported the screening of analogues of different scaffolds such as quinolines [40], cytidines [45] and andrographolides [46]. It's also common for repurposing efforts to propose drugs that are yet to be tested in vitro [13,32,[38][39][40][47][48][49][50][51][52][53].…”

Section: Introductionmentioning

confidence: 99%

In Silico Exploration of Bisphosphonate Scaffolds as Potential Inhibitors of SARS-CoV-2 RdRp for COVID-19 and PASC

Mohammed,

Chougule,

Ala

et al. 2023

Preprint

View full text Add to dashboard Cite

The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this paper. We have investigated bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates for further evaluation (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211). Interestingly, one of these (CHEMBL608526) very closely resembles the approved drug minodronate, and another (CHEMBL98211) resembles the approved drug zoledronate.

show abstract

Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach

Cited by 12 publications

References 65 publications

On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation

On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation

Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

In Silico Exploration of Bisphosphonate Scaffolds as Potential Inhibitors of SARS-CoV-2 RdRp for COVID-19 and PASC

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