Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases (CROSBI ID 280785)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Maraković, Nikola ; Knežević, Anamarija ; Rončević, Igor ; Brazzolotto, Xavier ; Kovarik, Zrinka ; Šinko, Goran
engleski
Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases
The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triplebinding 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 modelled using the PM7R6 method, stressing the importance of proton transfer from Nε of His438 to Oγ of Ser203 for achieving successful reactivation.
cholinesterase ; hydroxyiminoacetamide ; reactivation ; stereoselectivity ; PM7R6 method
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Podaci o izdanju
477
2020.
2771-2790
objavljeno
0264-6021
1470-8728
10.1042/bcj20200192
Povezanost rada
Farmacija, Javno zdravstvo i zdravstvena zaštita, Kemija