a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , MG , Brazil.
J Biomol Struct Dyn. 2015 Sep;33(9):2048-58. doi: 10.1080/07391102.2014.989408. Epub 2014 Dec 18.
Nerve agents are organophosphates acting as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine and, consequently, the termination of the transmission of nerve impulses. The inhibition of AChE by an organophosphate can be reversed by a nucleophilic agent able to dephosphorylate a serine residue in the active site of AChE. In this sense, the oximes are compounds capable of removing the nerve agent and reactivate the enzyme. Here, we have applied a methodology involving theoretical docking and Quantum Mechanics/Molecular Mechanics, using the softwares Molegro(®) and Spartan(®), to evaluate the kinetic constants of reactivation and the interactions of the oxime BI-6 with AChE inhibited by different organophosphorus compounds in comparison to in vitro data. Results confirm that this method is suitable for the prediction of kinetic and thermodynamic parameters of oximes, which may be useful in the design and selection of new and more effective oximes.
神经毒剂是作用于乙酰胆碱酯酶 (AChE) 的有机磷酸酯，AChE 是负责水解乙酰胆碱的酶，因此也是终止神经冲动传递的酶。有机磷酸酯对 AChE 的抑制可以被亲核试剂逆转，该亲核试剂能够使 AChE 活性部位的丝氨酸残基去磷酸化。从这个意义上说，肟类化合物能够去除神经毒剂并使酶重新活化。在这里，我们应用了一种涉及理论对接和量子力学/分子力学的方法，使用 Molegro(®) 和 Spartan(®) 软件，评估了不同有机磷化合物抑制的 AChE 与肟 BI-6 重新活化的动力学常数以及相互作用，与体外数据进行比较。结果证实，该方法适用于肟动力学和热力学参数的预测，这对于设计和选择新的、更有效的肟可能是有用的。
