Author/Editor		Maraković, Nikola; Knežević, Anamarija; Rončević, Igor; Brazzolotto, Xavier; Šinko, Goran
Title		Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases
Type		članek
Vol. and No.		Letnik 477, št. 15
Publication year		2020
Volume		str. 2771-2790
ISSN		0264-6021 - Biochemical journal
Language		eng
Abstract		The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr = 207 M-1 min-1) and III (kr = 213 M-1 min-1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from N[eta] of His438 to O[gamma] of Ser203 for achieving successful reactivation.
Keywords		PM7R6 method cholinesterase hydroxyiminoacetamide metoda PM7R6 holinesteraza hidroksiiminoacetamid