Investigating the potential of natural compounds as novel inhibitors of SARS-CoV-2 RdRP using computational approaches

Abstract

ABSTRACT COVID-19 is a highly contagious disease caused by SARS-CoV-2. Currently, no vaccines or antiviral treatments are available to combat this deadly virus; however, precautions and some repurposed medicines are available to contain COVID-19. RNA-dependent RNA polymerase (RdRP) plays an important role in the replication or transcription of viral mechanisms. Approved antiviral drug such as Remdesivir has shown inhibitory activity against SARS-CoV-2 RdRP. The purpose of this study was to carry out a rational screening of natural products against SARS-CoV-2 RdRP, which may serve as a basis to develop a treatment option against COVID-19. For this purpose, a protein and structure conservation analysis of SARS-CoV-2 RdRP was performed to check mutations. A library of 15,000 phytochemicals was developed from literature review, ZINC database, PubChem and MPD3 database; and was used to performed molecular docking and molecular dynamics simulation (MD) analysis. The top-ranked compounds were subjected to pharmacokinetic and pharmacological studies. Among them, top 7 compounds (Spinasaponin A, Monotropane, Neohesperidoe, Posin, Docetaxel, Psychosaponin B2, Daphnodrine M, and Target Remedesvir) were noticed to interact with the active site residues. MD simulation in aqueous solution suggested conformational flexibility of loop regions in the complex to stabilize the docked inhibitors. Our study revealed that the studied compounds have potential to bind to the active site residues of SARS-CoV-2 RdRP. Although, this computational work is not experimentally determined but the structural information and selected compounds might help in the design of antiviral drugs targeting SAR-CoV-2 by inhibiting the activity of SARS-CoV-2 RdRP.