Yang Jiawen, Chen Lin, Wang Shuo, Zhao Bing, Wang Ruige
College of Chemistry and Chemical Engineering, Qiqihar University, Qiqihar, 161006, People's Republic of China.
Heilongjiang Provincial Key Laboratory of Surface Active Agent and Auxiliary, Qiqihar University, Qiqihar, 161006, People's Republic of China.
Arch Toxicol. 2025 Mar 16. doi: 10.1007/s00204-025-04020-4.
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.
有机磷酸酯类农药（OPs）广泛应用于农业领域，可通过与酶活性位点的丝氨酸共价结合来抑制人类乙酰胆碱酯酶（hAChE）的活性。然而，其共价结合之外的分子识别机制仍不清楚。本研究采用分子对接结合分子动力学模拟（MD）来研究四种代表性的OPs，即磷胺、久效磷、敌敌畏和敌百虫，以及两种潜在的替代物厚朴酚（MAG）和和厚朴酚（HON），以了解hAChE的构象变化及其分子识别机制。结果表明，除了这些OPs外，所选替代物也会引起hAChE内部结构的各种变化，特别是与色氨酸86、酪氨酸124、酪氨酸337和组氨酸447周围关键残基的相互作用。利用MM-GBSA和SIE方法进行的能量计算进一步揭示了范德华相互作用在hAChE与这些OPs及其替代物相互作用中的关键作用。值得注意的是，两种潜在的农药替代物MAG和HON在苯环和羟基位置的结构与OPs不同，导致它们与hAChE的结合能较弱。此外，通过基于关键残基的虚拟定点诱变验证了模拟模型的准确性。通过识别动态结构变化和能量特征，本研究为寻找更安全的OPs替代物提供了有价值的信息。
