In this study, we systematically investigated the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective. Additionally, the effects of hydration on the proton transfer mechanism of the tautomeric forms of the halogenated favipiravir compounds are discussed. Our results suggest that spectroscopic properties allow for the elucidation of such tautomeric forms. As is well-known, the favipiravir compound has excellent antiviral properties and hence was recently tested for the treatment of new coronavirus (SARS-CoV-2). Through in silico modeling, in the current study, we evaluate the role of such tautomeric forms in order to consider the effect of drug-metabolism in the inhibition process of the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus. According to the molecular docking, all halogenated compounds presented a better interaction energy than the co-crystallized active ligand (-3.5 kcal mol-1) in the viral RdRp, in both wild-type (-6.3 to -6.5 kcal mol-1) and variant (-5.4 to -5.6 kcal mol-1) models. The variant analyzed for RdRp (Y176C) decreases the affinity of the keto form of the compounds in the active site, and prevented the ligands from interacting with RNA. These findings clearly indicated that all these compounds are promising as drug candidates for this molecular target.
- Publikační typ
- časopisecké články MeSH
Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.
- MeSH
- adenin škodlivé účinky analogy a deriváty metabolismus farmakologie MeSH
- adenosin škodlivé účinky analogy a deriváty metabolismus farmakologie MeSH
- adenosinmonofosfát škodlivé účinky analogy a deriváty metabolismus farmakologie MeSH
- alanin škodlivé účinky analogy a deriváty metabolismus farmakologie MeSH
- amidy škodlivé účinky metabolismus farmakologie MeSH
- antivirové látky škodlivé účinky metabolismus farmakologie MeSH
- chlorochin škodlivé účinky analogy a deriváty metabolismus farmakologie MeSH
- COVID-19 metabolismus MeSH
- dusíkaté sloučeniny škodlivé účinky metabolismus farmakologie MeSH
- farmakoterapie COVID-19 * MeSH
- lidé MeSH
- metabolické sítě a dráhy MeSH
- objevování léků * MeSH
- pyraziny škodlivé účinky metabolismus farmakologie MeSH
- pyrrolidiny škodlivé účinky metabolismus farmakologie MeSH
- racionální návrh léčiv MeSH
- ribavirin škodlivé účinky metabolismus farmakologie MeSH
- SARS-CoV-2 účinky léků metabolismus MeSH
- simulace molekulového dockingu MeSH
- thiazoly škodlivé účinky metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenin MeSH
- adenosin MeSH
- adenosinmonofosfát MeSH
- alanin MeSH
- amidy MeSH
- antivirové látky MeSH
- chlorochin MeSH
- dusíkaté sloučeniny MeSH
- favipiravir MeSH Prohlížeč
- galidesivir MeSH Prohlížeč
- nitazoxanide MeSH Prohlížeč
- pyraziny MeSH
- pyrrolidiny MeSH
- remdesivir MeSH Prohlížeč
- ribavirin MeSH
- thiazoly MeSH
