Naslov
Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases

Autori
Maraković, Nikola ; Knežević, Anamarija ; Rončević, Igor ; Brazzolotto, Xavier ; Kovarik, Zrinka ; Šinko, Goran

Izvornik
Biochemical Journal (0264-6021) 477 (2020); 2771-2790

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
cholinesterase ; hydroxyiminoacetamide ; reactivation ; stereoselectivity ; PM7R6 method

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Javno zdravstvo i zdravstvena zaštita, Farmacija

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