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

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.

Keywords: Favipiravir; RNA-dependent RNA polymerase (RdRp); Remdesivir; SARS-CoV-2; essramycin; non-structural proteins (NSP); triazolopyrimidine.

Figure 1

Phylogenetic tree of viral RdRp proteins.

Figure 2

Evaluation of the impact of the mutation on RdRp protein of SARS-CoV-2. (A) Apo RdRp protein (7BV1), and (B) Apo form of Remdesivir complex RdRp (7BV2); (i) represent the wild form, (ii) mutated form and (iii) superimposed structure of both proteins. (C,D) show the interatomic interaction by P323L of RdRp protein; (Ci,Di) represent the wild type of RdRp protein, (Cii,Dii) show proline to leucine substitution at 323 position.

Figure 3

Three-dimensional visualisation of docked complexes and protein–ligand hydrogen bond interactions: (A) SARS-CoV-2 RdRp/Comp-1, (B) SARS-CoV-2 RdRp/EMC-1, (C) SARS-CoV RdRp/Comp-1, and (D) SARS-CoV RdRp/EMC-1. Please refer to Supplementary Figure S2 for FP and REM–ligand interactions with SARS-CoV-2 RdRp and Figures S3 and S4 to visualise protein–ligand interactions of the individual complex.

Figure 4

The 3D interactions of Comp-1-NSP docked complexes. (A) NSP1, (B) NSP2, (C) NSP5, (D) NSP8, (E) NSP13, (F) NSP15 and (G) NSP3.

Figure 5

RMSD values of SARS-CoV-2 (A) and SARS-CoV (B) apo RdRp and docked complexes during 50 ns MD simulation.

Figure 6

RMSF values of SARS-CoV-2 (A) and SARS-CoV (B) apo RdRp and docked complexes during the 50 ns MD simulation.

Figure 7

R_g values of SARS-CoV-2 (A) and SARS-CoV (B) apo RdRp and docked complexes during 50 ns MD simulation.