Slight difference in the isomeric oximes K206 and K203 makes huge difference for the reactivation of organophosphorus-inhibited AChE: Theoretical and experimental aspects

Daniel A Polisel; Alexandre A de Castro; Daiana T Mancini; Elaine F F da Cunha; Tanos C C França; Teodorico C Ramalho; Kamil Kuca

doi:10.1016/j.cbi.2019.05.037

Slight difference in the isomeric oximes K206 and K203 makes huge difference for the reactivation of organophosphorus-inhibited AChE: Theoretical and experimental aspects

Chem Biol Interact. 2019 Aug 25:309:108671. doi: 10.1016/j.cbi.2019.05.037. Epub 2019 Jun 15.

Authors

Daniel A Polisel¹, Alexandre A de Castro¹, Daiana T Mancini¹, Elaine F F da Cunha², Tanos C C França³, Teodorico C Ramalho⁴, Kamil Kuca⁵

Affiliations

¹ Department of Chemistry, Federal University of Lavras, Lavras, Brazil.
² Department of Chemistry, Federal University of Lavras, Lavras, Brazil; Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Rio de Janeiro, Brazil.
³ Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Rio de Janeiro, Brazil; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic.
⁴ Department of Chemistry, Federal University of Lavras, Lavras, Brazil; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic. Electronic address: teo@ufla.br.
⁵ Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic. Electronic address: kamil.kuca@uhk.cz.

PMID: 31207225
DOI: 10.1016/j.cbi.2019.05.037

Abstract

Studies with oximes have been extensively developed to design new reactivators with better efficiency, and greater spectrum of action. In this study, we aimed to analyze the influence of the Carbamoyl group position change in two isomeric oximes, K203 and K206, on the reactivation percentage of Mus musculus Acetylcholinesterase (MmAChE), inhibited by different nerve agents. Theoretical calculations were performed to assess the difference for the oxime activity with inhibited AChE-complexes and the factors that govern this difference. Comparing theoretical and experimental data, it is possible to observe that this change between the oximes results in different reactivation percentage for the same nerve agent, due to the different interaction modes and activation energy for the studied systems.

Keywords: K203; K206; Mechanistic studies; Nerve agents; Reactivator.

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism*
Animals
Binding Sites
Cholinesterase Reactivators / chemistry*
Cholinesterase Reactivators / metabolism
Drug Design
Mice
Molecular Docking Simulation
Nerve Agents / chemistry
Nerve Agents / metabolism
Organophosphorus Compounds / chemistry*
Organophosphorus Compounds / metabolism
Organothiophosphorus Compounds / chemistry
Organothiophosphorus Compounds / metabolism
Oximes / chemistry*
Quantum Theory
Thermodynamics

Substances

Cholinesterase Reactivators
Nerve Agents
Organophosphorus Compounds
Organothiophosphorus Compounds
Oximes
VX
Acetylcholinesterase