Preliminary Computational Analysis of Pyrazinamide-Based Derivatives Reveals Possible Inhibition of SARS-CoV-2 RNA-Dependent RNA Polymerase, and Their Possible Use as Antiviral Agents
DOI:
https://doi.org/10.48048/tis.2022.3918Keywords:
Pyrazinamide, Favipiravir, In silico analysis, COVID-19, SARS-CoV-2, RNA-dependent RNA polymeraseAbstract
Pyrazinamide is a pyrazine analog currently used to treat tuberculosis. It shares a core structure similar to that of favipiravir, which is a promising drug candidate that may inhibit the SARS-CoV-2 RNA-dependent RNA polymerase. This feature could be an opportunity for further drug development of anti-COVID-19 medication starting from a pyrazinamide core structure. This study aimed to determine and predict the most effective pyrazinamide-based analogs against the SARS-CoV-2 RNA-dependent RNA polymerase by using combined ligand- and structure-based computational analysis. This study performed a rational in silico study to screen pyrazinamide-like molecules from a commercially available ZINC database, with a similarity score higher than 0.40, and then these screened for acceptable pharmacokinetic properties, and then to further conduct molecular docking analysis with SARS-CoV-2 RNA-dependent RNA polymerase. The results showed that compound 12, having a dichloropyrimidine core structure had a similarity score of 0.446. It exerted the most binding affinity with RNA-dependent RNA polymerase, with estimated docking scores of −5.72, −5.25, −7.06, −7.00 and −4.63 kcal/mol in intact, ribosylated, mono-phosphoribosylated, di-phosphoribosylated and tri-phosphoribosylated forms, respectively. Watson-Crick base-pairing of compound 12 indicated that it favored binding with the uracil nucleoside of the RNA template. Compound 12 was confirmed as the lead compound, being a pyrazinamide-like molecule, and so might be a most promising candidate molecule, as an adenine analog RNA-dependent RNA polymerase inhibitor. It is suggested that the antiviral effect of this lead compound should be studied further as part of a drug discovery and development process.
HIGHLIGHTS
- In silico analysis was performed to screen pyrazinamide-like compounds against the RNA-dependent RNA polymerase
- Pharmacokinetics and drug-likeliness properties of fourteen preselected compounds were assessed by using SwissADME with favorable results
- Among these preselected compounds, compound 12 showed the best docking score in almost all of its phosphoribosylated forms
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