An In Silico Stereo-electronic Comparison of Conventional Pyridinium Oximes and K-oximes for Organophosphate (OP) Poisoning

Apurba K. Bhattacharjee, Kamil Kuca, Kamil Musilek, Richard K. Gordon

Abstract

A comparative analysis of stereo-electronic properties of five cholinesterase reactivators (pralidoxime (2- PAM), trimedoxime, obidoxime, HI-6, and HLo-7) and six “K-oximes” was performed to assess their roles in reactivating OP-inhibited phosphorylated serine residue of mouse AChE. Quantum mechanical (QM) calculations starting from semiempirical to ab initio levels were sequentially performed with hierarchical basis sets to obtain the individual optimized geometry and stereo-electronic properties of the eleven oximes. Next, solvation effects were computed on the optimized structures using two different (PCM and COSMO) QM models. Results indicate that properties, such as the distance between the bisquarternary nitrogen atoms, surface area, molecular volume, and hydrophilicity have important roles in the reactivation of OP-inhibited AChE. Electronic attributes, such as the molecular electrostatic potentials and orbital energies were also found to be important parameters for reactivation. Nucleophilicity of the oxygen atoms at the terminal regions, electrophilicity in the central regions of the oximes, and location of the molecular orbitals on aromatic rings have significant roles for the experimentally observed reactivations in several OP agents inhibited mouse AChE. Analysis of solvation free energy indicates high solute polarization and dispersion energies of the oximes to be particularly critical for the tabun- inhibited mouse AChE, whereas lower values of these properties favor reactivation against other OP agents, such as soman, sarin and cyclosarin. Feature mappings of our recently reported pharmacophore model were also observed to be consistent with the above observed electronic properties. In silico toxicity evaluation on these oximes predicts the Koximes to have somewhat higher oral toxicity compared to the other bispyridinium oximes.

Keywords: Stereoelectronic features, oximes, nerve agents, OP-inhibited AChE, modeling, Poisoning, Quantum mechanical, pharmacophore, energy, bispyridinium oximes