PMID- 30424582 OWN - NLM STAT- MEDLINE DCOM- 20190116 LR - 20231004 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 23 IP - 11 DP - 2018 Nov 12 TI - Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon. LID - 10.3390/molecules23112954 [doi] LID - 2954 AB - 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. FAU - de Paula, Reuel L AU - de Paula RL AUID- ORCID: 0000-0002-1033-179X AD - National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Gracas 50, Duque de Caxias 25250-020, Brazil. reuel.lp@gmail.com. AD - IDQBRN (Brazilian Army CBRN Defense Institute), Avenida das Americas 28705, Rio de Janeiro 23020-470, Brazil. reuel.lp@gmail.com. FAU - de Almeida, Joyce S F D AU - de Almeida JSFD AUID- ORCID: 0000-0002-1426-6681 AD - Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praca General Tiburcio 80, Rio de Janeiro 22290-270, Brazil. joycesfdalmeida@gmail.com. FAU - Cavalcante, Samir F A AU - Cavalcante SFA AD - IDQBRN (Brazilian Army CBRN Defense Institute), Avenida das Americas 28705, Rio de Janeiro 23020-470, Brazil. samir.cavalcante@eb.mil.br. AD - Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro (UFRJ), CCS Bloco H Cidade Universitaria, Rio de Janeiro 21941-902, Brazil. samir.cavalcante@eb.mil.br. FAU - Goncalves, Arlan S AU - Goncalves AS AUID- ORCID: 0000-0002-5965-3191 AD - Federal Institute of Education, Science and Technology, Avenida Ministro Salgado Filho S/N, Vila Velha 29106-010, Brazil. arlansgoncalves@gmail.com. FAU - Simas, Alessandro B C AU - Simas ABC AD - Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro (UFRJ), CCS Bloco H Cidade Universitaria, Rio de Janeiro 21941-902, Brazil. abcsimas@nppn.ufrj.br. FAU - Franca, Tanos C C AU - Franca TCC AUID- ORCID: 0000-0002-6048-8103 AD - Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praca General Tiburcio 80, Rio de Janeiro 22290-270, Brazil. tanosfranca@gmail.com. AD - Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic. tanosfranca@gmail.com. FAU - Valis, Martin AU - Valis M AD - Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Kralove and University Hospital, Simkova 870, 50003 Hradec Kralove, Czech Republic. Valismar@seznam.cz. FAU - Kuca, Kamil AU - Kuca K AUID- ORCID: 0000-0001-9664-1109 AD - Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic. kamil.kuca@uhk.cz. FAU - Nepovimova, Eugenie AU - Nepovimova E AD - Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic. evzenie.n@seznam.cz. FAU - Granjeiro, Jose M AU - Granjeiro JM AD - National Institute of Metrology, Quality and Technology (INMETRO), Avenida Nossa Senhora das Gracas 50, Duque de Caxias 25250-020, Brazil. jmgranjeiro@gmail.com. LA - eng PT - Journal Article DEP - 20181112 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (Cholinesterase Inhibitors) RN - 0 (Cholinesterase Reactivators) RN - 0 (Oximes) RN - Q9CX8P80JW (Paraoxon) SB - IM MH - Cholinesterase Inhibitors/*pharmacology MH - Cholinesterase Reactivators/*chemistry/*pharmacology MH - Erythrocytes/drug effects/enzymology MH - *Models, Molecular MH - Molecular Docking Simulation MH - Molecular Dynamics Simulation MH - Molecular Structure MH - Oximes/*chemistry/*pharmacology MH - Paraoxon/*chemistry/*pharmacology PMC - PMC6278417 OTO - NOTNLM OT - Ellman's method OT - TOPSIS-AHP OT - acetylcholinesterase OT - molecular modeling OT - multicriteria decision making OT - neutral oxime COIS- The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. EDAT- 2018/11/15 06:00 MHDA- 2019/01/17 06:00 PMCR- 2018/11/12 CRDT- 2018/11/15 06:00 PHST- 2018/09/28 00:00 [received] PHST- 2018/11/07 00:00 [revised] PHST- 2018/11/09 00:00 [accepted] PHST- 2018/11/15 06:00 [entrez] PHST- 2018/11/15 06:00 [pubmed] PHST- 2019/01/17 06:00 [medline] PHST- 2018/11/12 00:00 [pmc-release] AID - molecules23112954 [pii] AID - molecules-23-02954 [pii] AID - 10.3390/molecules23112954 [doi] PST - epublish SO - Molecules. 2018 Nov 12;23(11):2954. doi: 10.3390/molecules23112954.