Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp)
(2022) In Molecules 27(3).- 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... (More)
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 Favipi-ravir 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.
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- author
- Karthic, Anandakrishnan ; Kesarwani, Veerbhan ; Singh, Rahul Kunwar ; Yadav, Pavan Kumar ; Chaturvedi, Navaneet ; Chauhan, Pallavi LU ; Yadav, Brijesh Singh and Kushwaha, Sandeep Kumar
- organization
- publishing date
- 2022-02-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Essramycin, Favipiravir, Non-structural proteins (NSP), Remdesivir, RNA-dependent RNA polymerase (RdRp), SARS-CoV-2, Triazolopyrimidine
- in
- Molecules
- volume
- 27
- issue
- 3
- article number
- 801
- publisher
- MDPI AG
- external identifiers
-
- scopus:85123528412
- pmid:35164069
- ISSN
- 1420-3049
- DOI
- 10.3390/molecules27030801
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
- id
- 9729c799-ba9a-4e27-9f84-650ef8d4c508
- date added to LUP
- 2022-02-15 17:16:49
- date last changed
- 2024-06-13 10:42:35
@article{9729c799-ba9a-4e27-9f84-650ef8d4c508,
abstract = {{<p>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 Favipi-ravir 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.</p>}},
author = {{Karthic, Anandakrishnan and Kesarwani, Veerbhan and Singh, Rahul Kunwar and Yadav, Pavan Kumar and Chaturvedi, Navaneet and Chauhan, Pallavi and Yadav, Brijesh Singh and Kushwaha, Sandeep Kumar}},
issn = {{1420-3049}},
keywords = {{Essramycin; Favipiravir; Non-structural proteins (NSP); Remdesivir; RNA-dependent RNA polymerase (RdRp); SARS-CoV-2; Triazolopyrimidine}},
language = {{eng}},
month = {{02}},
number = {{3}},
publisher = {{MDPI AG}},
series = {{Molecules}},
title = {{Computational Analysis Reveals Monomethylated Triazolopyrimidine as a Novel Inhibitor of SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp)}},
url = {{http://dx.doi.org/10.3390/molecules27030801}},
doi = {{10.3390/molecules27030801}},
volume = {{27}},
year = {{2022}},
}