The targeted pesticides as acetylcholinesterase inhibitors: comprehensive cross-organism molecular modelling studies performed to anticipate the pharmacology of harmfulness to humans in vitro

Commercially available pesticides were examined as Mus musculus and Homo sapiens acetylcholinesterase (mAChE and hAChE) inhibitors by means of ligand-based (LB) and structure-based (SB) in silico approaches. Initially, the crystal structures of simazine, monocrotophos, dimethoate, and acetamiprid were reproduced using various force fields. Subsequently, LB alignment rules were assessed and applied to determine the inter synaptic conformations of atrazine, propazine, carbofuran, carbaryl, tebufenozide, imidacloprid, diuron, monuron, and linuron. Afterwards, molecular docking and dynamics SB studies were performed on either mAChE or hAChE, to predict the listed pesticides’ binding modes. Calculated energies of global minima (Eglob_min) and free energies of binding (∆Gbinding) were correlated with the pesticides’ acute toxicities (i.e., the LD50values) against mice, as well to generate the model that could predict the LD50s against humans. Although for most of the pesticides the low Eglob_mincorrelates with the high acute toxicity, it is the ∆Gbindingthat conditions the LD50values for all the evaluated pesticides. Derived pLD50= f(∆Gbinding) mAChE model may predict the pLD50against hAChE, too. The hAChE inhibition by atrazine, propazine, and simazine (the most toxic pesticides) was elucidated by SB quantum mechanics (QM) DFT mechanistic and concentration-dependent kinetic studies, enriching the knowledge for design of less toxic pesticides.