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

Abdulwahed Alrehaily; Abdo A Elfiky; Ibrahim M Ibrahim; Mohamed N Ibrahim; Amr Sonousi

doi:10.1038/s41598-023-49712-y

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

Sci Rep. 2023 Dec 27;13(1):23080. doi: 10.1038/s41598-023-49712-y.

Authors

Abdulwahed Alrehaily¹, Abdo A Elfiky², Ibrahim M Ibrahim³, Mohamed N Ibrahim⁴, Amr Sonousi^{5

6}

Affiliations

¹ Biology Department, Faculty of Science, Islamic University of Madinah, 42351, Madinah, Saudi Arabia.
² Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt. abdo@sci.cu.edu.eg.
³ Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
⁴ Clinical Laboratories Department, College of Applied Medical Sciences, Jouf University, Qurrayat, Saudi Arabia.
⁵ Pharmaceutical Organic Department, Faculty of Pharmacy, Cairo University, Giza, Egypt.
⁶ University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo, Egypt.

Abstract

The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and human health, and the emerging resistant variants are an ongoing threat. One essential protein to target to prevent virus replication is the viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, a uridine nucleotide analog that potently inhibits viral polymerase, has been found to help treat SARS-CoV-2 patients. This work combines molecular docking and dynamics simulation (MDS) to test 14 sofosbuvir-based modifications against SARS-CoV-2 RdRp. The results reveal comparable (slightly better) average binding affinity of five modifications (compounds 3, 4, 11, 12, and 14) to the parent molecule, sofosbuvir. Compounds 3 and 4 show the best average binding affinities against SARS-CoV-2 RdRp (- 16.28 ± 5.69 and - 16.25 ± 5.78 kcal/mol average binding energy compared to - 16.20 ± 6.35 kcal/mol for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. The present study proposes compounds 3 and 4 as potential SARS-CoV-2 RdRp blockers, although this has yet to be proven experimentally.

MeSH terms

Antiviral Agents / chemistry
COVID-19*
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
RNA, Viral
RNA-Dependent RNA Polymerase / genetics
SARS-CoV-2 / genetics
Sofosbuvir* / chemistry
Sofosbuvir* / pharmacology

Substances

Sofosbuvir
Antiviral Agents
RNA, Viral
RNA-Dependent RNA Polymerase