Novel adenosine derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective

Amr Sonousi; Hanan A Mahran; Ibrahim M Ibrahim; Mohamed N Ibrahim; Abdo A Elfiky; Wael M Elshemey

doi:10.1007/s43440-021-00300-9

Novel adenosine derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective

Pharmacol Rep. 2021 Dec;73(6):1754-1764. doi: 10.1007/s43440-021-00300-9. Epub 2021 Jun 24.

Authors

Amr Sonousi^{1

2}, Hanan A Mahran³, Ibrahim M Ibrahim³, Mohamed N Ibrahim^{4

5}, Abdo A Elfiky⁶, Wael M Elshemey^{3

7}

Affiliations

¹ Pharmaceutical Organic Department, Faculty of Pharmacy, Cairo University, Giza, Egypt.
² University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo, Egypt.
³ Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt.
⁴ Clinical Laboratories Department, College of Applied Medical Sciences, Jouf University, Sakakah, Kingdom of Saudi Arabia.
⁵ Microbiology Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
⁶ Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt. abdo@sci.cu.edu.eg.
⁷ Physics Department, Faculty of Science, Islamic University of Madinah, Medina, Kingdom of Saudi Arabia.

Abstract

Background: SARS-CoV-2 is a newly emerged human coronavirus that severely affected human health and the economy. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target to stop virus replication. The adenosine derivative, remdesivir, was authorized for emergency use 10 months ago by the United States FDA against COVID-19 despite its doubtful efficacy against SARS-CoV-2.

Methods: A dozen modifications based on remdesivir are tested against SARS-CoV-2 RdRp using combined molecular docking and dynamics simulation in this work.

Results: The results reveal a better binding affinity of 11 modifications compared to remdesivir. Compounds 8, 9, 10, and 11 show the best binding affinities against SARS-CoV-2 RdRp conformations gathered during 100 ns of the Molecular Dynamics Simulation (MDS) run (- 8.13 ± 0.45 kcal/mol, - 8.09 ± 0.67 kcal/mol, - 8.09 ± 0.64 kcal/mol, and - 8.07 ± 0.73 kcal/mol, respectively).

Conclusions: The present study suggests these four compounds as potential SARS-CoV-2 RdRp inhibitors, which need to be validated experimentally.

Keywords: Computational drug design; Medicinal; Nucleotide inhibitors; RdRp; Remdesivir; SARS-CoV-2.

MeSH terms

Adenosine / analogs & derivatives*
Adenosine Monophosphate / analogs & derivatives*
Adenosine Monophosphate / chemistry
Alanine / analogs & derivatives*
Alanine / chemistry
Antiviral Agents / chemistry*
Binding Sites
COVID-19
Computer Simulation
Coronavirus RNA-Dependent RNA Polymerase / antagonists & inhibitors*
Coronavirus RNA-Dependent RNA Polymerase / chemistry
Drug Design*
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
SARS-CoV-2 / pathogenicity

Substances

Antiviral Agents
remdesivir
Adenosine Monophosphate
Coronavirus RNA-Dependent RNA Polymerase
NSP12 protein, SARS-CoV-2
Adenosine
Alanine