Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras 37200-000, MG, Brazil.
Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, 500 03 Hradec Kralove, Czech Republic.
Molecules. 2024 Aug 3;29(15):3684. doi: 10.3390/molecules29153684.
Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.
神经毒剂是有机磷酸酯 (OPs)，它们作为乙酰胆碱酯酶 (AChE) 的强效抑制剂起作用，AChE 是负责水解乙酰胆碱的酶。抑制后，磷酸化丝氨酸的脱烷基反应，即 AChE 的老化，可以发生。当老化时，OP 抑制的 AChE 的重激活剂不再有效。因此，老化的 AChE 的再烷化可能提供了一种逆转 AChE 老化的途径。在这项研究中，进行了分子建模以提出新的配体作为老化 AChE 的重烷化剂。我们应用了一种涉及对接和量子力学/分子力学 (QM/MM) 计算的方法来评估复活动力学常数和配体与 OP 老化的 AChE 的相互作用，并将其与文献中发现的数据进行比较。所得结果证实，该方法适用于预测配体的动力学和热力学参数，这对于设计和选择新的更有效的 AChE 再烷化剂可能是有用的。
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