engleski

Modeling of a Michaelis type complex between phosphorylated acetylcholinesterase and an oxime via a reactivation product the phosphorylated oxime

During the past decades, tremendous work was done in research on reactivators of acetylcholinesterase inhibited by organophosphorus compounds involving different laboratories. At the present, only four antidotes are in use in therapy for poisoning by OPs: 2-PAM, HI-6, obidoxime and trimedoxime. Numerous compounds have been designed and synthetized to be more effective reactivators than those currently in use. Many of those new compounds fail at the enzyme level because interactions formed within the AChE active site are not favourable ones that lead to a successful reactivation. The approach in which the modeling of a phosphorylated oxime, a product of successful reactivation in the AChE active site, may be a way to better understand the role of active site residues during the process of formation of the Michaelis type of complex between an enzyme and oxime. After reactivation, a change in phosphorus stereochemistry occurs leading to a different spatial arrangement of attached radicals, now including an oxime. To study interactions between the AChE oxyanion hole and a phosphorylated oxime, an S203G mutant was used to avoid the steric hindrance caused by the catalytic serine. In this way, the phosphorylated oxime could be positioned close to the oxyanion hole. In the final step, the oxime without a phosphoester moiety was transferred in the phosphorylated AChE and molecular dynamics was used to test the stability of the Michaelis type of complex including an oxime position near the phosphorylated serine.

acetylcholinesterase ; oxime, in silico modeling, Michaelis type of complex

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