Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp)

Anandakrishnan Karthic,Pallavi Chauhan,Veerbhan Kesarwani,Navaneet Chaturvedi,Rahul Kunwar Singh,Pavan Kumar Yadav,Brijesh Singh Yadav,Sandeep Kumar Kushwaha

doi:10.3390/molecules27030801

Abstract

The human population is still facing appalling conditions due to several outbreaks of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus. The absence of specific drugs, appropriate vaccines for mutants, and knowledge of potential therapeutic agents makes this situation more difficult. Several 1, 2, 4-triazolo [1, 5-a] pyrimidine (TP)-derivative compounds were comprehensively studied for antiviral activities against RNA polymerase of HIV, HCV, and influenza viruses, and showed immense pharmacological interest. Therefore, TP-derivative compounds can be repurposed against the RNA-dependent RNA polymerase (RdRp) protein of SARS-CoV-2. In this study, a meta-analysis was performed to ensure the genomic variability and stability of the SARS-CoV-2 RdRp protein. The molecular docking of natural and synthetic TP compounds to RdRp and molecular dynamic (MD) simulations were performed to analyse the dynamic behaviour of TP compounds at the active site of the RdRp protein. TP compounds were also docked against other non-structural proteins (NSP1, NSP2, NSP3, NSP5, NSP8, NSP13, and NSP15) of SARS-CoV-2. Furthermore, the inhibition potential of TP compounds was compared with Remdesivir and Favipiravir drugs as a positive control. Additionally, TP compounds were analysed for inhibitory activity against SARS-CoV RdRp protein. This study demonstrates that TP analogues (monomethylated triazolopyrimidine and essramycin) represent potential lead molecules for designing an effective inhibitor to control viral replication. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-CoV-2.

Highlights

The SARS-CoV-2 virus is still developing new variants that cause infection, such as Omicron, the most recent global SARS-CoV-2 variant [1]
We computationally evaluated the inhibition potential of four TP-based ligands, one parent TP compound (triazolopyrimidine (TPP-1), two natural derivatives (essramycin (EMC-1) and monomethylated triazolopyrimidine (Comp-1)), and one synthetic TP derivative (MTP stereoisomer (TBP-2)) against RNA-dependent RNA polymerase (RdRp) and non-structural proteins of SARS-CoV-2
Various research studies have been performed since the pandemic began in late 2019. None of these studies explored the potential of triazolopyrimidine or its derivatives against SARS-CoV-2 [36,37,38]

Summary

Introduction

The SARS-CoV-2 virus is still developing new variants that cause infection, such as Omicron, the most recent global SARS-CoV-2 variant [1]. The lack of rapid, responsive, and inexpensive diagnostic methods for SARS-CoV-2 infection are posing more severe challenges to humanity [2]. There are currently no commercially licensed drugs available, except for Remdesivir, 2-DG, and pegylated Interferon alpha-2b, to combat against the SARS-CoV-2 virus [3,4,5]. In April 2021, rates of infection and fatalities climbed steadily, especially in India. This is highly concerning because the human population remains vulnerable in many countries, even after massive vaccination drives. The concomitant usage of multiple therapeutic options can help to reduce the disease burden [6,7]

Methods

Results

Discussion

Conclusion