Covalent Inhibitors from Saudi Medicinal Plants Target RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2

Ahmed H Bakheit; Quaiser Saquib; Sarfaraz Ahmed; Sabiha M Ansari; Abdullah M Al-Salem; Abdulaziz A Al-Khedhairy

doi:10.3390/v15112175

Covalent Inhibitors from Saudi Medicinal Plants Target RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2

Viruses. 2023 Oct 30;15(11):2175. doi: 10.3390/v15112175.

Authors

Ahmed H Bakheit¹, Quaiser Saquib², Sarfaraz Ahmed³, Sabiha M Ansari⁴, Abdullah M Al-Salem², Abdulaziz A Al-Khedhairy²

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
² Zoology Department, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
³ Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁴ Botany & Microbiology Department, College of Sciences, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Abstract

COVID-19, a disease caused by SARS-CoV-2, has caused a huge loss of human life, and the number of deaths is still continuing. Despite the lack of repurposed drugs and vaccines, the search for potential small molecules to inhibit SARS-CoV-2 is in demand. Hence, we relied on the drug-like characters of ten phytochemicals (compounds 1-10) that were previously isolated and purified by our research team from Saudi medicinal plants. We computationally evaluated the inhibition of RNA-dependent RNA polymerase (RdRp) by compounds 1-10. Non-covalent (reversible) docking of compounds 1-10 with RdRp led to the formation of a hydrogen bond with template primer nucleotides (A and U) and key amino acid residues (ASP623, LYS545, ARG555, ASN691, SER682, and ARG553) in its active pocket. Covalent (irreversible) docking revealed that compounds 7, 8, and 9 exhibited their irreversible nature of binding with CYS813, a crucial amino acid in the palm domain of RdRP. Molecular dynamic (MD) simulation analysis by RMSD, RMSF, and Rg parameters affirmed that RdRP complexes with compounds 7, 8, and 9 were stable and showed less deviation. Our data provide novel information on compounds 7, 8, and 9 that demonstrated their non-nucleoside and irreversible interaction capabilities to inhibit RdRp and shed new scaffolds as antivirals against SARS-CoV-2.

Keywords: COVID-19; MD simulation; RdRp; SARS-CoV-2; docking; medicinal plants; phytochemicals.

MeSH terms

Amino Acids
Antiviral Agents* / pharmacology
Molecular Docking Simulation
Molecular Dynamics Simulation
Plants, Medicinal* / chemistry
RNA-Dependent RNA Polymerase* / antagonists & inhibitors
SARS-CoV-2* / drug effects
Saudi Arabia

Substances

Amino Acids
Antiviral Agents
RNA-Dependent RNA Polymerase

Grants and funding

5-21-01-001-0025/This research was funded by King Abdulaziz City for Science and Technology (KACST) via the Fast Track Funding Path for COVID-19 Research Projects, grant number 5-21-01-001-0025.