Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 2; p. 192
• Main Authors: da Silva, Jorge Alberto Valle, Pereira, Ander Francisco, LaPlante, Steven R, Kuca, Kamil, Ramalho, Teodorico Castro, França, Tanos Celmar Costa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 27.01.2020; MDPI AG
• Subjects: 2-pam; Acetylcholinesterase; Acetylcholinesterase - chemistry; Acetylcholinesterase - drug effects; Catalytic Domain; Humans; Life Sciences; Molecular Conformation; Molecular Dynamics Simulation; Organothiophosphorus Compounds; Organothiophosphorus Compounds - pharmacology; Pralidoxime Compounds; Pralidoxime Compounds - chemistry; Pralidoxime Compounds - pharmacology; Protons; qm/mm method; Quantum Theory; Serine; Serine - chemistry; QM/MM method; acetylcholinesterase; VX; 2-PAM
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10020192

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human ( ) acetylcholinesterase ( AChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (S 2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of AChE.