Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

b Skaggs School of Pharmacy and Pharmaceutical Sciences University of California at San Diego San Diego CA USA

c Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro RJ 22290 270 Brazil d Department of Chemistry and Biochemistry Concordia University Montreal QC Canada e Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Kralove Hradec Kralove Czech Republic

Laboratory of Molecular Modeling Chemistry Department Federal University of Lavras Lavras MG 37200 000 Brazil

Laboratory of Molecular Modeling Chemistry Department Federal University of Lavras Lavras MG 37200 000 Brazil e Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Kralove Hradec Kralove Czech Republic

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