Repurposing drugs for treatment of SARS-CoV-2 infection: computational design insights into mechanisms of action

Kandwal, Shubhangi; Fayne, Darren

doi:10.1080/07391102.2020.1825232

Cited by 16 publications

(9 citation statements)

References 94 publications

(110 reference statements)

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“…SBDD has been shown as an advanced approach for the discovery and refinement of therapeutic agents 21,[47][48][49][50][51][52][53][54] because it is quite difficult and costly to examine the interaction of many compounds with enzymes at the molecular level under experimental conditions. Thus, these computational methods are providing a significant advantage in the hit identification phase of the costly drug discovery process.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have reported that N proteins will be important candidates for drug-targeting in other CoVs as they process various critical functions, such as RNA genomic packing, viral replication and transcription, and assembly in infectious cells. 21,22,25,29,30,[44][45][46][47][48] Few in silico studies have attempted to design a new drug targeting to inhibit interactions between the SARS-CoV-2 N and RNA at the molecular level. For instance, Sarma et al showed that theophylline and pyrimidine drug groups, 21 while Amin et al 49 showed that chloroquine and hydroxychloroquine drug groups are effective against SARS-CoV-2 N-NTD domain.…”

Section: Discussionmentioning

confidence: 99%

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Computational drug repurposing study of the RNA binding domain of SARS‐CoV‐2 nucleocapsid protein with antiviral agents

Tatar

Ozyurt

Turhan

2020

Biotechnology Progress

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The recent outbreak of coronavirus disease (COVID‐19) in China caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to worldwide human infections and deaths. The nucleocapsid (N) protein of coronaviruses (CoVs) is a multifunctional RNA binding protein necessary for viral RNA replication and transcription. Therefore, it is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. This study addresses the potential to repurpose antiviral compounds approved or in development for treating human CoV induced infections against SARS‐CoV‐2 N. For this purpose, we used the docking methodology to better understand the inhibitory mechanism of this protein with the existing 34 antiviral compounds. The results of this analysis indicate that rapamycin, saracatinib, camostat, trametinib, and nafamostat were the top hit compounds with binding energy (−11.87, −10.40, −9.85, −9.45, −9.35 kcal/mol, respectively). This analysis also showed that the most common residues that interact with the compounds are Phe66 , Arg68 , Gly69 , Tyr123 , Ile131 , Trp132 , Val133 , and Ala134 . Subsequently, protein‐ligand complex stability was examined with molecular dynamics simulations for these five compounds, which showed the best binding affinity. According to the results of this study, the interaction between these compounds and crucial residues of the target protein were maintained. These results suggest that these residues are potential drug targeting sites for the SARS‐CoV‐2 N protein. This study information will contribute to the development of novel compounds for further in vitro and in vivo studies of SARS‐CoV‐2, as well as possible new drug repurposing strategies to treat COVID‐19 disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Computational drug repurposing study of the RNA binding domain of SARS‐CoV‐2 nucleocapsid protein with antiviral agents

Tatar

Ozyurt

Turhan

2020

Biotechnology Progress

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“…Relative to remdesivir, the 11 obtained compounds from the virtual screening and MD simulations derived from the ZINC database displayed significant interactions with all RdRp active site residues (Ghazwani et al, 2021). Based on pharmacophore modeling of the remdesivir/RdRp complex (two anionic acceptor, one donor, one acceptor, and one dual donor and acceptor features), the epigallocatechin gallate, kuromanin, procyanidin-b-2, and rutin were the top four hits among 5,836 compounds from the ChEMBL database (Kandwal and Fayne, 2020). Pharmacophore modeling, structure-based virtual screening, and MD simulations of RdRp bound with the known RdRp inhibitors were used to screen the potential agents from the six databases; PubChem-134297651, CHEMBL387201, CHEMBL1196124, PubChem-122704503, ZINC257357489, and ZINC5605331, which were highly interacting with RdRp at the ATP binding pocket (Grzybowski et al, 2002).…”

Section: Rna-dependent Rna Polymerasementioning

confidence: 99%

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies

et al. 2022

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Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug–gene pairs (atazanavir–UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz–CYP2B6; nevirapine–HLA, CYP2B6, ABCB1; lopinavir–SLCO1B3, ABCC2; ribavirin–SLC28A2; tocilizumab–FCGR3A; ivermectin–ABCB1; oseltamivir–CES1, ABCB1; clopidogrel–CYP2C19, ABCB1, warfarin–CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)–CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug–drug interactions (DDIs) and drug–herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug–gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.

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“…The above observations strongly suggested that Nsp16-Nsp10 may be a crucial drug target for highly specific anti-coronavirus drugs in comparison to the viral MTase active site (Rosas-Lemus et al, 2020). Several interesting studies have already been done by considering Nsp16-Nsp10 as an effective drug target for SARS-CoV-2 inhibition (Cavasotto & Di Filippo, 2020;Culletta et al, 2020;Kadioglu et al, 2020;Kandwal & Fayne, 2020;Tazikeh-Lemeski et al, 2020).…”

Section: Introductionmentioning

confidence: 96%

Identification of naphthyridine and quinoline derivatives as potential Nsp16-Nsp10 inhibitors: a pharmacoinformatics study

Aldahham

Al-Khafaji

Saleh

et al. 2020

Journal of Biomolecular Structure and Dynamics

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This research is a recent effort to explore some new heterocyclic compounds as novel and potential nonstructural protein-16-nonstructural protein-10 (Nsp16-Nsp10) inhibitors for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibition. The SARS-CoV-2 is causative agent of coronavirus disease 2019 (COVID-19) pandemic. A set of 58 molecules belongs to the naphthyridine and quinoline derivatives have been recently synthesized and considered for structure-based virtual screening against Nsp16-Nsp10. Molecular docking was virtually performed to screen for anti-SARS-CoV-2 activity against Nsp16-Nsp10. Fourteen out of fifty-eight compounds were exhibited binding affinity higher than co-crystal bound ligand s-adenosylmethionine (SAM) toward Nsp16-Nsp10. Further, the in silico pharmacokinetics assessment was carried out and it was found that two molecules possess the acceptable pharmacokinetic profile, hence considered promising Nsp16-Nsp10 inhibitors. The binding interaction analysis was revealed some crucial binding interactions between the final selected two molecules and ligand-binding amino acid residues of Nsp16-Nsp10 protein. In order to explore the characteristics of the protein-ligand complex and how selected small molecules retained inside the receptor cavity in dynamic states, all-atoms conventional molecular dynamics (MD) simulation was performed. Several factors were obtained from the MD simulation trajectory evidently suggested the potentiality of the molecules and stability of the protein-ligand complex. Finally, the binding affinity of both molecules and SAM was explored through the MM-GBSA approach which explained that both molecules possess strong affection towards the Nsp16-Nsp10. Hence, from the pharmacoinformatics assessment, it can be concluded that both heterocyclic compounds might be crucial for SARS-CoV-2 inhibition, subjected to experimental validation.

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Repurposing drugs for treatment of SARS-CoV-2 infection: computational design insights into mechanisms of action

Cited by 16 publications

References 94 publications

Computational drug repurposing study of the RNA binding domain of SARS‐CoV‐2 nucleocapsid protein with antiviral agents

Computational drug repurposing study of the RNA binding domain of SARS‐CoV‐2 nucleocapsid protein with antiviral agents

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies

Identification of naphthyridine and quinoline derivatives as potential Nsp16-Nsp10 inhibitors: a pharmacoinformatics study

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