Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon

  • Molecules. 2018 Nov 12;23(11):2954. doi: 10.3390/molecules23112954.
Reuel L de Paula  1  2 ,  Joyce S F D de Almeida  3 ,  Samir F A Cavalcante  4  5 ,  Arlan S Gonçalves  6 ,  Alessandro B C Simas  7 ,  Tanos C C Franca  8  9 ,  Martin Valis  10 ,  Kamil Kuca  11 ,  Eugenie Nepovimova  12 ,  José M Granjeiro  13
Affiliations
  • 1. National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Graças 50, Duque de Caxias 25250-020, Brazil. [email protected].
  • 2. IDQBRN (Brazilian Army CBRN Defense Institute), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil. [email protected].
  • 3. Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil. [email protected].
  • 4. IDQBRN (Brazilian Army CBRN Defense Institute), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil. [email protected].
  • 5. Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro (UFRJ), CCS Bloco H Cidade Universitária, Rio de Janeiro 21941-902, Brazil. [email protected].
  • 6. Federal Institute of Education, Science and Technology, Avenida Ministro Salgado Filho S/N, Vila Velha 29106-010, Brazil. [email protected].
  • 7. Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro (UFRJ), CCS Bloco H Cidade Universitária, Rio de Janeiro 21941-902, Brazil. [email protected].
  • 8. Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil. [email protected].
  • 9. Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic. [email protected].
  • 10. Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Simkova 870, 50003 Hradec Králové, Czech Republic. [email protected].
  • 11. Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic. [email protected].
  • 12. Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic. [email protected].
  • 13. National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Graças 50, Duque de Caxias 25250-020, Brazil. [email protected].
PMID: 30424582 DOI: 10.3390/molecules23112954
Abstract

The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman's modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood⁻brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies.

Keywords
Ellman’s method; TOPSIS-AHP; acetylcholinesterase; molecular modeling; multicriteria decision making; neutral oxime.
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