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.

Details

Title
Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon
Author
de Paula, Reuel L 1   VIAFID ORCID Logo  ; Joyce S F D de Almeida 2   VIAFID ORCID Logo  ; Cavalcante, Samir F A 3 ; Gonçalves, Arlan S 4   VIAFID ORCID Logo  ; Simas, Alessandro B C 5 ; Franca, Tanos C C 6   VIAFID ORCID Logo  ; Valis, Martin 7 ; Kuca, Kamil 8   VIAFID ORCID Logo  ; Nepovimova, Eugenie 8 ; Granjeiro, José M 9 

1  National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Graças 50, Duque de Caxias 25250-020, Brazil; Brazilian Army CBRN Defense Institute (IDQBRN), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil 
2  Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil 
3  Brazilian Army CBRN Defense Institute (IDQBRN), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; 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 
4  Federal Institute of Education, Science and Technology, Avenida Ministro Salgado Filho S/N, Vila Velha 29106-010, Brazil 
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 
6  Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic 
7  Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Simkova 870, 50003 Hradec Králové, Czech Republic 
8  Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic 
9  National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Graças 50, Duque de Caxias 25250-020, Brazil 
First page
2954
Publication year
2018
Publication date
2018
Publisher
MDPI AG
e-ISSN
14203049
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.3390/molecules23112954
ProQuest document ID
2582845912
Copyright
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.