Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon
Reuel L. de Paula,
Joyce S. F. D. de Almeida,
Samir F. A. Cavalcante,
Arlan S. Gonçalves,
Alessandro B. C. Simas,
Tanos C. C. Franca,
Martin Valis,
Kamil Kuca,
Eugenie Nepovimova,
José M. Granjeiro
Affiliations
Reuel L. de Paula
National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Graças 50, Duque de Caxias 25250-020, Brazil
Joyce S. F. D. de Almeida
Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil
Samir F. A. Cavalcante
Brazilian Army CBRN Defense Institute (IDQBRN), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil
Arlan S. Gonçalves
Federal Institute of Education, Science and Technology, Avenida Ministro Salgado Filho S/N, Vila Velha 29106-010, Brazil
Alessandro B. C. Simas
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
Tanos C. C. Franca
Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil
Martin Valis
Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Simkova 870, 50003 Hradec Králové, Czech Republic
Kamil Kuca
Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic
Eugenie Nepovimova
Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic
José M. Granjeiro
National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Graças 50, Duque de Caxias 25250-020, Brazil
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.
