triple-binding reactivator of organophosphate-inhibited cholinesterases. Nikola Marakovic, Anamarija Knezevic, Igor Roncevic, Xavier Brazzolotto4, Zrinka Kovarik and Goran Sinko
1 structure: 6T9S: Structure of human butyrylcholinesterase in complex with S enantiomer of oxime III, methylimidazole derivative of 2-hydroxyimino-N-(azidophenylpropyl)acetamide
Title: Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases Marakovic N, Knezevic A, Roncevic I, Brazzolotto X, Kovarik Z, Sinko G Ref: Biochemical Journal, 477:2771, 2020 : PubMed
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=207M-1min-1) and III (kr=213M-1min-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 Nsigma of His438 to Ogamma of Ser203 for achieving successful reactivation.
