Quantum chemical and steered molecular dynamics studies for one pot solution to reactivate aged acetylcholinesterase with alkylator oxime

Dimethyl(pyridin-2-yl)sulfonium based oxime has been designed to reverse the aging process of organophosphorus inhibited AChE and to reactivate the aged-AChE adduct. We have employed DFT M05-2X/6-31G* level of theory in aqueous phase with polarizable continuum solvation model (PCM) for the methylation of phosphonate ester monoanion of the soman-aged adduct. The calculated free energy of activation for the methyl transfer process from designed dimethyl(phenyl)sulfonium (1) to aged AChE-OP adduct occurs with a barrier of 31.4 kcal/mol at M05-2X/6-31G* level of theory, which is 6.4 kcal/mol lower compared to the aging process signifies the preferential reversal process to recover the aged AChE-OP adduct. The pyridine ring containing alkylated sulfonium species, dimethyl(pyridin-2-yl)sulfonium (2), reduced the free energy of activation by 4.4 kcal/mol compared to the previously reported alkylating agent N-methyl-2-methoxypyridinium species (A) for the alkylation of aged AChE-OP adduct. The free enzyme can be liberated from the inhibited acetylcholinesterase with the sulfonium compound decorated with an oxime group to avoid the administration of oxime drugs separately. The calculated potential energy surfaces show that the oxime based sulfonium compound (3) can effectively methylate the aged phosphonate ester monoanion of soman aged-adduct. The calculated global reactivity descriptors of the oxime 3 also shed light on this observation. To gain better understanding for protein drug interaction as well as the unbinding and conformational changes of the drug candidate in the active site of cholinesterase, steered molecular dynamics (SMD) simulation with 3 has been performed. Through a protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometrical and the orientation of drug-like candidate, the oxime 3 suggests to orchestrate the better reactivation process. The docking studies have been performed with 3 in the aged AChE and BChE to obtain the initial geometry of the SMD studies. The docking methods adopted in this study have been verified with the available crystal geometry of 1-methyl-2-(pentafluorobenzyloxyimino)pyridinium compound in aged soman inhibited human BChE (PDB code: 4B0P). The computational study suggests that the newly designed oxime is a potential candidate to reactivate the aged-AChE adduct. (C) 2014 Elsevier Ireland Ltd. All rights reserved.