engleski

Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates

The library of nearly 300 novel uncharged oxime reactivators was used to select lead reactivators of human acetylcholinesterase (hAChE) covalently conjugated with sarin, cyclosarin, VX, paraoxon and tabun. N-substituted 2-hydroxyiminoacetamido alkylamines were identified as best reactivators [1] and reactivation kinetics of the lead oxime RS41A analyzed in detail. Compared to reference pyridinium reactivators 2PAM and MMB4 molecular recognition of RS41A reflected in its Kox constant was determined to be compromised on average by an order of magnitude for different OP-hAChE conjugates., without significant differences in the first order maximal fosforilation rate constant k2. Systematic structural modifications of the RS41A lead resulted in the several-fold better reactivator RS194B. Kinetic analysis indicated Kox reduction for RS194B as the main kinetic parameter enhancement leading towards more efficient reactivation. Comparative omputational molecular modeling of RS41A and RS194B interactions with VX inhibited hAChE, bound reversibly in Michaelis type complex and covalently in pentacoordinate transition state indicated larger similarity of binding geometries between the two states for RS194B than for RS41A rationalizing the faster reactivation reaction as a consequence of lowering interaction energies needed for formation of both reaction states. References: [1] Sit et al. Journal of Biological Chemistry, 2011, 286, 19422-19430.

sarin; cyclosarin; VX; paraoxon; tabunRS41A; k2; Kox

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