Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase

Elfiky, Abdo A.; Mahran, Hanan A.; Ibrahim, Ibrahim M.; Ibrahim, Mohamed N.; Elshemey, Wael M.

doi:10.1039/d1ra07447d

Cited by 10 publications

(8 citation statements)

References 50 publications

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“…Thus, SASA profiles signified the conformational changes that might have happened during the protein-ligand interactions. The results obtained were in agreement with the previous studies [62] , [63] . According to the MM-PBSA free energy calculated between RdRp and the ligands, the binding free energy (ΔG bind) of RdRp-Fidaxomicin (—334.2±16.7 kj/mol) was stronger than that of RdRp-Rifabutin (—326.5±13.6 kj/mol), which was in line with the results of docking and MD simulation.…”

Section: Resultssupporting

confidence: 93%

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

Gangadharan

Ambrose²,

Rajajagadeesan³

et al. 2022

Journal of Infection and Public Health

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Section: Resultssupporting

confidence: 93%

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

Gangadharan

Ambrose²,

Rajajagadeesan³

et al. 2022

Journal of Infection and Public Health

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“…Other attempts against MPro were done [ 130 , 131 , 132 , 133 ] but require further experimental data to validate the hypothesis. The RNA polymerase, [ 134 ] as well as the nucleocapsid, [ 135 ] and envelope protein [ 136 ] were proposed as a druggable target, but these studies will require further confirmation by experimental data to verify whether NSPs could be considered viable targets.…”

Section: Molecular Dynamics Insights On New Sars‐cov‐2 Variantsmentioning

confidence: 99%

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

et al. 2022

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The SARS‐CoV‐2 virus is responsible for the COVID‐19 pandemic the world experience since 2019. The protein responsible for the first steps of cell invasion, the spike protein, has probably received the most attention in light of its central role during infection. Computational approaches are among the tools employed by the scientific community in the enormous effort to study this new affliction. One of these methods, namely molecular dynamics (MD), has been used to characterize the function of the spike protein at the atomic level and unveil its structural features from a dynamic perspective. In this review, we focus on these main findings, including spike protein flexibility, rare S protein conformational changes, cryptic epitopes, the role of glycans, drug repurposing, and the effect of spike protein variants.

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“…Defant et al synthesized several nucleoside-like compounds from a cellulose pyrolysis product and identified a nucleotide analog among those compounds that was more promising as RdRp inhibitors than remdesivir by molecular docking and MD simulations [ 72 ]. Sonousi et al [ 73 ] and Elfiky et al [ 74 ] identified several ATP derivatives and guanosine triphosphate (GTP) derivatives that had stronger affinities for RdRp than RemTP using molecular docking, MM-GBSA calculations, and MD simulations. Arba et al performed molecular docking, MD simulations, and MM-PBSA calculations to study the binding mode and binding affinities of 3′ modified analogs of RemTP for nsp12 with an RNA duplex [ 75 ].…”

Section: Molecular Simulation Studies On Inhibition Mechanisms Of Nuc...mentioning

confidence: 99%

“…Their simulation results were consistent with previous experimental results [ 77 , 78 , 79 ] and elucidated the detailed inhibition mechanisms of 2′ substituted nucleotide analogs against SARS-CoV-2 RdRp. Another simulation study also indicated the effectiveness of adding a bulky group at the 2′ position of the ribose ring to improve the inhibitory effects of nucleotide analogs [ 74 ].…”

Section: Molecular Simulation Studies On Inhibition Mechanisms Of Nuc...mentioning

confidence: 99%

“…The simulation studies reviewed here elucidated the atomic level mechanisms of the delayed chain termination of remdesivir, immediate chain termination of 2′ and 3′ modified nucleotide analogs, and template-dependent inhibition of remdesivir. Furthermore, these simulation studies also suggested more promising nucleotide analogs for inhibiting the function of RdRp than remdesivir [ 72 , 73 , 74 , 75 ]. All simulation studies focused on the situation after NTPs or nucleotide analogs are incorporated into the binding site of RdRp.…”

Section: Molecular Simulation Studies On Inhibition Mechanisms Of Nuc...mentioning

confidence: 99%

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State-of-the-Art Molecular Dynamics Simulation Studies of RNA-Dependent RNA Polymerase of SARS-CoV-2

Tanimoto

Itoh

Okumura

2022

IJMS

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Molecular dynamics (MD) simulations are powerful theoretical methods that can reveal biomolecular properties, such as structure, fluctuations, and ligand binding, at the level of atomic detail. In this review article, recent MD simulation studies on these biomolecular properties of the RNA-dependent RNA polymerase (RdRp), which is a multidomain protein, of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are presented. Although the tertiary structures of RdRps in SARS-CoV-2 and SARS-CoV are almost identical, the RNA synthesis activity of RdRp of SARS-CoV is higher than SARS-CoV-2. Recent MD simulations observed a difference in the dynamic properties of the two RdRps, which may cause activity differences. RdRp is also a drug target for Coronavirus disease 2019 (COVID-19). Nucleotide analogs, such as remdesivir and favipiravir, are considered to be taken up by RdRp and inhibit RNA replication. Recent MD simulations revealed the recognition mechanism of RdRp for these drug molecules and adenosine triphosphate (ATP). The ligand-recognition ability of RdRp decreases in the order of remdesivir, favipiravir, and ATP. As a typical recognition process, it was found that several lysine residues of RdRp transfer these ligand molecules to the binding site such as a “bucket brigade.” This finding will contribute to understanding the mechanism of the efficient ligand recognition by RdRp. In addition, various simulation studies on the complexes of SARS-CoV-2 RdRp with several nucleotide analogs are reviewed, and the molecular mechanisms by which these compounds inhibit the function of RdRp are discussed. The simulation studies presented in this review will provide useful insights into how nucleotide analogs are recognized by RdRp and inhibit the RNA replication.

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Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase

Abstract: According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting +250 M people.

Cited by 10 publications

References 50 publications

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

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

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

State-of-the-Art Molecular Dynamics Simulation Studies of RNA-Dependent RNA Polymerase of SARS-CoV-2

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