Molecular docking and molecular dynamics simulations revealed interaction mechanism of acetylcholinesterase with organophosphorus pesticides and their alternatives.

Organophosphate pesticides (OPs) are widely used in agricultural fields and can inhibit the activity of human acetylcholinesterase (hAChE) by covalently binding to serine at the enzyme's active site. However, the molecular recognition mechanisms beyond their covalent binding remain unclear. This study employed molecular docking along with molecular dynamics simulations (MD) to investigate four representative OPs, Phosphamidon, Monocrotophos, Dichlorvos, and Trichlorfon, as well as two potential alternatives Magnolol (MAG) and Honokiol (HON), to understand the conformational change of hAChE and its molecular recognition mechanism. The results indicate that, in addition to these OPs, the selected substitutes also induce various changes in the internal structure of hAChE, especially interactions with key residues around Trp86, Tyr124, Tyr337, and His447. Energy calculations utilizing MM-GBSA and SIE methods further reveal the critical role of van der Waals interactions in hAChE's interaction with these OPs and their substitutes. It is worth noting that two potential pesticide alternatives MAG and HON differ in structure from OPs at the benzene ring and hydroxyl positions, resulting in their weaker binding energy with hAChE. Furthermore, the accuracy of simulation models was validated through in silico site-directed mutagenesis based on the key residues. By identifying dynamic structural changes and energy signatures, this study provides valuable information for finding safer alternatives to OPs.