a Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMCBD) Military Institute of Engineering , Rio de Janeiro , Brazil.
b Faculty of Technology , University of the State of Rio de Janeiro , Resende , Brazil.
J Biomol Struct Dyn. 2018 May;36(6):1430-1438. doi: 10.1080/07391102.2017.1324322. Epub 2017 May 18.
Tabun is one of the most dangerous nerve agents because it has deleterious effects like inhibition of the essential enzymes acetylcholinesterase (AChE) and butyrylcholinesterase. Some oximes such HI6 as 2-PAM are nucleophiles that are capable to reactivate inhibited human AChE under some conditions. Zwitterionic and cationic species have the best chance of productive action on inhibited AChE. However uncharged oximes can give important interaction information. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed molecular docking simulations and molecular dynamics and calculated binding energies of complexes of these compounds with human AChE. The uncharged oximes of larger structure were more susceptible to the influence of the substituents on the phosphorus atom and presented low binding energies. In contrast, HI 6 and 2-PAM showed high binding energy values with great contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of the oximes/AChE tabun-inhibited complexes.
沙林是最危险的神经毒剂之一，因为它会对人体造成有害影响，例如抑制重要的酶乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶。一些肟类化合物，如 HI6 和 2-PAM，是亲核试剂，在某些条件下能够使被抑制的人 AChE 重新活化。两性离子和阳离子物种对抑制的 AChE 具有最佳的有效作用机会。然而，不带电荷的肟类化合物可以提供重要的相互作用信息。为了研究阳离子和不带电荷肟类化合物的相互作用和行为，我们进行了分子对接模拟和分子动力学计算，并计算了这些化合物与人类 AChE 形成复合物的结合能。结构较大的不带电荷肟类化合物更容易受到磷原子上取代基的影响，表现出较低的结合能。相比之下，HI6 和 2-PAM 与 AChE 形成复合物的结合能值较高，并且氨基酸 Asp74 的贡献很大，这表明季氮原子对肟类化合物/AChE 沙林抑制复合物的亲和力和相互作用非常重要。
