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Updated: Jun 13, 2025

Screening for Thermotoga maritima Membrane-Bound Pyrophosphatase Inhibitors
Published on: November 23, 2019
Mechanistic Insights into Enhanced Reactivation of Organophosphate-Inhibited Enzymes by Methyl-Substituted
Phiphob Naweephattana1, Nalinee Kongkaew2, Panida Surawatanawong3
1Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Abstract:
Organophosphate (OP) compounds, such as paraoxon (POX), inhibit enzymes critical for neurotransmission, causing severe neurotoxic effects. Pralidoxime (2-pyridine aldoxime methyl chloride) or 2-PAM is commonly employed to reverse this inhibition, but its reactivation efficiency is limited. This study computationally explores the reactivation mechanisms of 2-PAM and its methyl-substituted analogs, 4-methyl-2-PAM (4-Met-2-PAM), and 4,6-dimethyl-2-PAM (4,6-Dimet-2-PAM). The reactivation process involves several key steps, such as hydrogen transfer and nucleophilic substitution (SN2). Introducing methyl groups at positions 4 and 6 increases the negative charge on the oxime oxygen, improving nucleophilicity and reactivity. Both 4-Met-2-PAM and 4,6-Dimet-2-PAM show better reactivity than 2-PAM, with 4,6-Dimet-2-PAM demonstrating the greatest improvement. This enhanced reactivity shifts the rate-determining step from nucleophilic substitution to the initial hydrogen transfer. These findings offer valuable insights for designing more effective oxime-based antidotes for organophosphate poisoning.
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