Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp)
Open Access
- 26 January 2022
- Vol. 27 (3), 801
- https://doi.org/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.This publication has 52 references indexed in Scilit:
- g_mmpbsa—A GROMACS Tool for High-Throughput MM-PBSA CalculationsJournal of Chemical Information and Modeling, 2014
- Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom TypingJournal of Chemical Information and Modeling, 2012
- admetSAR: A Comprehensive Source and Free Tool for Assessment of Chemical ADMET PropertiesJournal of Chemical Information and Modeling, 2012
- CD-HIT: accelerated for clustering the next-generation sequencing dataBioinformatics, 2012
- Structural basis for active site closure by the poliovirus RNA-dependent RNA polymeraseProceedings of the National Academy of Sciences of the United States of America, 2010
- Recent Progress in 1,2,4-Triazolo[1,5-a]pyrimidine ChemistryAdvances in Heterocyclic Chemistry, 2007
- GROMACS: Fast, flexible, and freeJournal of Computational Chemistry, 2005
- Personal Experience with Four Kinds of Chemical Structure Drawing Software: Review on ChemDraw, ChemWindow, ISIS/Draw, and ChemSketchJournal of Chemical Information and Computer Sciences, 2004
- BLAST: at the core of a powerful and diverse set of sequence analysis toolsNucleic Acids Research, 2004
- CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choiceNucleic Acids Research, 1994